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1.  Association between Folate Intake and the Risk of Lung Cancer: A Dose-Response Meta-Analysis of Prospective Studies 
PLoS ONE  2014;9(4):e93465.
Studies have reported inconsistent results regarding the existence of an association between folate intake and the risk of lung cancer. The purpose of this study was to summarize the evidence from prospective cohort studies regarding this relationship by using a dose-response meta-analytic approach.
Methodology and Principal Findings
In September 2013, we performed electronic searches in PubMed, Embase, and the Cochrane Library to identify studies examining the effect of folate intake on the incidence of lung cancer. Only prospective cohort studies that reported the effect estimates about the incidence of lung cancer with 95% confidence intervals (CIs) for more than 2 categories of folate intake were included. Overall, we examined 9 cohort studies reporting the data of 566,921 individuals. High folate intake had little effect on the risk of lung cancer (risk ratio [RR], 0.92; 95% CI, 0.84–1.01; P = 0.076). Dose-response meta-analysis also suggested that a 100 µg/day increase in folate intake had no significant effect on the risk of lung cancer (RR, 0.99; 95% CI, 0.97–1.01; P = 0.318). Subgroup analysis suggested that the potential protective effect of low folate intake (100–299 µg/day) was more evident in women than men, while the opposite was true of high folate intake (>400 µg/day). Finally, subgroup analyses of a 100 µg/day increment in folate intake indicated that its potential protective effect was more evident in men than in women.
Our study revealed that folate intake had little or no effect on the risk of lung cancer. Subgroup analyses indicated that an increased folate intake was associated with a reduced risk of lung cancer in men. Furthermore, low folate intake may be a protective factor for women, and high folate intake for men.
PMCID: PMC3979671  PMID: 24713625
2.  The Proteomic Response to Mutants of the Escherichia coli RNA Degradosome 
Molecular bioSystems  2013;9(4):750-757.
The Escherichia coli RNA degradosome recognizes and degrades RNA through the coordination of four main protein components, the endonuclease RNase E, the exonuclease PNPase, the RhlB helicase and the metabolic enzyme enolase. To help our understanding of the functions of the RNA degradosome, we quantified expression changes of >2,300 proteins by mass spectrometry based shotgun proteomics in E. coli strains deficient in rhlB, eno, pnp (which displays temperature sensitive growth), or rne(1-602) which encodes a C-terminal truncation mutant of RNaseE and is deficient in degradosome assembly. Global protein expression changes are most similar between the pnp and rhlB mutants, confirming the functional relationship between the genes. We observe down-regulation of protein chaperones including GroEL and DnaK (which associate with the degradosome), a decrease in translation related proteins in Δpnp, ΔrhlB and rne(1-602) cells, and a significant increase in the abundance of aminoacyl-tRNA synthetases. Analysis of the observed proteomic changes point to a shared motif, CGCTGG, that may be associated with RNA degradosome targets. Further, our data provide information on the expression modulation of known degradosome-associated proteins, such as DeaD and RNase G, as well as other RNA helicases and RNases – suggesting or confirming functional complementarity in some cases. Taken together, our results emphasize the role of the RNA degradosome in the modulation of the bacterial proteome and provide the first large-scale proteomic description of the response to perturbation of this major pathway of RNA degradation.
PMCID: PMC3709862  PMID: 23403814
3.  Deletion of miRNAs in bone marrow prevents streptozotocin-induced murine autoimmune diabetes but deletion of miR-155 does not 
Cell Cycle  2013;12(7):1151-1152.
PMCID: PMC3646871  PMID: 23528982
Dicer; miRNAs; type 1 diabetes; streptozotocin; mir-155; knockout mouse
4.  Vibrio parahaemolyticus, Southern Coastal Region of China, 2007–2012 
Emerging Infectious Diseases  2014;20(4):685-688.
We analyzed the prevalence and characteristics of Vibrio parahaemolyticus among patients with acute infectious diarrhea in the southern coastal region of China. V. parahaemolyticus was the leading cause of bacterial infectious diarrhea in this region during 2007–2012. Serotype O3:K6 strains were most common, followed by serotypes O4:K8 and O3:K29.
PMCID: PMC3966377  PMID: 24655369
Vibrio parahaemolyticus; infectious diarrhea; epidemic; China; bacteria; Vibrio
5.  Enhanced Thermal Stability and Hydrolytic Ability of Bacillus subtilis Aminopeptidase by Removing the Thermal Sensitive Domain in the Non-Catalytic Region 
PLoS ONE  2014;9(3):e92357.
Besides the catalytic ability, many enzymes contain conserved domains to perform some other physiological functions. However, sometimes these conserved domains were unnecessary or even detrimental to the catalytic process for industrial application of the enzymes. In this study, based on homology modeling and molecular dynamics simulations, we found that Bacillus subtilis aminopeptidase contained a thermal sensitive domain (protease-associated domain) in the non-catalytic region, and predicted that deletion of this flexible domain can enhance the structure stability. This prediction was then verified by the deletion of protease-associated domain from the wild-type enzyme. The thermal stability analysis showed that deletion of this domain improved the T50 (the temperature required to reduce initial activity by 50% in 30 min) of the enzyme from 71°C to 77°C. The melting temperature (Tm) of the enzyme also increased, which was measured by thermal denaturation experiments using circular dichroism spectroscopy. Further studies indicated that this deletion did not affect the activity and specificity of the enzyme toward aminoacyl-p-nitroanilines, but improved its hydrolytic ability toward a 12-aa-long peptide (LKRLKRFLKRLK) and soybean protein. These findings suggested the possibility of a simple technique for enzyme modification and the artificial enzyme obtained here was more suitable for the protein hydrolysis in food industry than the wild-type enzyme.
PMCID: PMC3954873  PMID: 24633010
6.  TLR3 activation efficiency by high or low molecular mass poly I:C 
Innate immunity  2012;19(2):184-192.
Toll-like receptor 3 (TLR3) plays a critical role in initiating type I IFN-mediated innate immunity against viral infections. TLR3 recognizes various forms of double stranded (ds) RNA, including viral dsRNA and a synthetic mimic of dsRNA, poly I:C, which has been used extensively as a TLR3 ligand to induce antiviral immunity. The activation efficiency of TLR3 by poly I:C is influenced by various factors, including size of the ligands, delivery methods and cell types. In this study, we examined the stimulatory effect of two commercially-available poly I:Cs [high molecular mass (HMM) and low molecular mass (LMM)] on TLR3 activation in various human cell types by determining the induction of type I and type III IFNs, as well as the antiviral effect. We demonstrated that the direct addition of both HMM- and LMM-poly I:C to the cultures of primary macrophages or a neuroplastoma cell line could activate TLR3. However, the transfection of poly I:C was necessary to induce TLR3 activation in other cell types studied. In all the cell lines tested, the efficiency of TLR3 activation by HMM-poly I:C was significantly higher than that by LMM-poly I:C. These observations indicate the importance and necessity of developing effective TLR3 ligands for antiviral therapy.
PMCID: PMC3942089  PMID: 23035017
TLR3; poly I:C; type I IFN; type III IFN; LyoVec
7.  Dynamics of Potassium Release and Adsorption on Rice Straw Residue 
PLoS ONE  2014;9(2):e90440.
Straw application can not only increase crop yields, improve soil structure and enrich soil fertility, but can also enhance water and nutrient retention. The aim of this study was to ascertain the relationships between straw decomposition and the release-adsorption processes of K+. This study increases the understanding of the roles played by agricultural crop residues in the soil environment, informs more effective straw recycling and provides a method for reducing potassium loss. The influence of straw decomposition on the K+ release rate in paddy soil under flooded condition was studied using incubation experiments, which indicated the decomposition process of rice straw could be divided into two main stages: (a) a rapid decomposition stage from 0 to 60 d and (b) a slow decomposition stage from 60 to 110 d. However, the characteristics of the straw potassium release were different from those of the overall straw decomposition, as 90% of total K was released by the third day of the study. The batches of the K sorption experiments showed that crop residues could adsorb K+ from the ambient environment, which was subject to decomposition periods and extra K+ concentration. In addition, a number of materials or binding sites were observed on straw residues using IR analysis, indicating possible coupling sites for K+ ions. The aqueous solution experiments indicated that raw straw could absorb water at 3.88 g g−1, and this rate rose to its maximum 15 d after incubation. All of the experiments demonstrated that crop residues could absorb large amount of aqueous solution to preserve K+ indirectly during the initial decomposition period. These crop residues could also directly adsorb K+ via physical and chemical adsorption in the later period, allowing part of this K+ to be absorbed by plants for the next growing season.
PMCID: PMC3938734  PMID: 24587364
8.  In Site Bioimaging of Hydrogen Sulfide Uncovers Its Pivotal Role in Regulating Nitric Oxide-Induced Lateral Root Formation 
PLoS ONE  2014;9(2):e90340.
Hydrogen sulfide (H2S) is an important gasotransmitter in mammals. Despite physiological changes induced by exogenous H2S donor NaHS to plants, whether and how H2S works as a true cellular signal in plants need to be examined. A self-developed specific fluorescent probe (WSP-1) was applied to track endogenous H2S in tomato (Solanum lycopersicum) roots in site. Bioimaging combined with pharmacological and biochemical approaches were used to investigate the cross-talk among H2S, nitric oxide (NO), and Ca2+ in regulating lateral root formation. Endogenous H2S accumulation was clearly associated with primordium initiation and lateral root emergence. NO donor SNP stimulated the generation of endogenous H2S and the expression of the gene coding for the enzyme responsible for endogenous H2S synthesis. Scavenging H2S or inhibiting H2S synthesis partially blocked SNP-induced lateral root formation and the expression of lateral root-related genes. The stimulatory effect of SNP on Ca2+ accumulation and CaM1 (calmodulin 1) expression could be abolished by inhibiting H2S synthesis. Ca2+ chelator or Ca2+ channel blocker attenuated NaHS-induced lateral root formation. Our study confirmed the role of H2S as a cellular signal in plants being a mediator between NO and Ca2+ in regulating lateral root formation.
PMCID: PMC3937356  PMID: 24587333
9.  Estimates of Forest Biomass Carbon Storage in Liaoning Province of Northeast China: A Review and Assessment 
PLoS ONE  2014;9(2):e89572.
Accurate estimates of forest carbon storage and changes in storage capacity are critical for scientific assessment of the effects of forest management on the role of forests as carbon sinks. Up to now, several studies reported forest biomass carbon (FBC) in Liaoning Province based on data from China's Continuous Forest Inventory, however, their accuracy were still not known. This study compared estimates of FBC in Liaoning Province derived from different methods. We found substantial variation in estimates of FBC storage for young and middle-age forests. For provincial forests with high proportions in these age classes, the continuous biomass expansion factor method (CBM) by forest type with age class is more accurate and therefore more appropriate for estimating forest biomass. Based on the above approach designed for this study, forests in Liaoning Province were found to be a carbon sink, with carbon stocks increasing from 63.0 TgC in 1980 to 120.9 TgC in 2010, reflecting an annual increase of 1.9 TgC. The average carbon density of forest biomass in the province has increased from 26.2 Mg ha−1 in 1980 to 31.0 Mg ha−1 in 2010. While the largest FBC occurred in middle-age forests, the average carbon density decreased in this age class during these three decades. The increase in forest carbon density resulted primarily from the increased area and carbon storage of mature forests. The relatively long age interval in each age class for slow-growing forest types increased the uncertainty of FBC estimates by CBM-forest type with age class, and further studies should devote more attention to the time span of age classes in establishing biomass expansion factors for use in CBM calculations.
PMCID: PMC3934887  PMID: 24586881
10.  Establishment and Validation of an Updated Diagnostic FCM Scoring System Based on Pooled Immunophenotyping in CD34+ Blasts and Its Clinical Significance for Myelodysplastic Syndromes 
PLoS ONE  2014;9(2):e88706.
Abnormal immunophenotypes of hematopoietic cells can be detected by flow cytometry (FCM) to assist the diagnosis of myelodysplastic syndromes (MDS). We previously established a FCM scoring system for the diagnosis of low-grade MDS. In this study, additional valuable antigens were involved in an updated FCM scoring system (u-FCMSS) for all MDS subtypes. The u-FCMSS showed better sensitivity and specificity (89.4% and 96.5%) in distinguishing MDS from non-clonal cytopenia diseases. Validation analysis of u-FCMSS exhibited comparable sensitivity and specificity (86.7% and 93.3%) and high agreement rate (88.9%) of FCM diagnosis with morphological diagnosis at optimal cut-off (score 3). The distribution of FCM scores in different disease stages was also analyzed. The results suggested that early scoring from abnormal expression of mature myeloid/lymphoid antigens and advanced scoring from abnormal expression of stem/progenitor antigens expression constituted the majority of FCM scores of low-grade and high-grade MDS, respectively. High early scoring was generally accompanied by low IPSS-R score and superior survival, whereas high advanced scoring was accompanied by high IPSS-R score and inferior survival. In addition, the low-risk MDS patients with high early scoring and low advanced scoring were revealed as candidates for immunosuppressive therapy, whereas those with high advanced scoring and low early scoring may be more suitable for decitabine treatment. In conclusion, the u-FCMSS is a useful tool for diagnosis, prognosis and treatment selection in MDS. Differences in classes of antigens expressed and in distribution of FCM scores may reflect distinctive stage characteristics of MDS during disease progression.
PMCID: PMC3928275  PMID: 24558415
11.  Selective Small Molecule Targeting β-Catenin Function Discovered by In Vivo Chemical Genetic Screen 
Cell reports  2013;4(5):898-904.
Canonical Wnt signaling pathway, mediated by the transcription factor β-catenin, plays critical roles in embryonic development, and represents an important therapeutic target. In a zebrafish-based in vivo screen for small molecules that specifically perturb embryonic dorsoventral patterning, we discovered a novel compound, named windorphen, which selectively blocks the Wnt signal required for ventral development. Windorphen exhibits remarkable specificity toward β-catenin-1 function, indicating that the two β-catenin isoforms found in zebrafish are not functionally redundant. We show that windorphen is a selective inhibitor of p300 histone acetyl transferase, a co-activator that associates with β-catenin. Lastly, windorphen robustly and selectively kills cancer cells that harbor Wnt-activating mutations, supporting the therapeutic potential of this novel Wnt inhibitor class.
PMCID: PMC3923627  PMID: 24012757
12.  A genome-wide association study identifies common variants influencing serum uric acid concentrations in a Chinese population 
BMC Medical Genomics  2014;7:10.
Uric acid (UA) is a complex phenotype influenced by both genetic and environmental factors as well as their interactions. Current genome-wide association studies (GWASs) have identified a variety of genetic determinants of UA in Europeans; however, such studies in Asians, especially in Chinese populations remain limited.
A two-stage GWAS was performed to identify single nucleotide polymorphisms (SNPs) that were associated with serum uric acid (UA) in a Chinese population of 12,281 participants (GWAS discovery stage included 1452 participants from the Dongfeng-Tongji cohort (DFTJ-cohort) and 1999 participants from the Fangchenggang Area Male Health and Examination Survey (FAMHES). The validation stage included another independent 8830 individuals from the DFTJ-cohort). Affymetrix Genome-Wide Human SNP Array 6.0 chips and Illumina Omni-Express platform were used for genotyping for DFTJ-cohort and FAMHES, respectively. Gene-environment interactions on serum UA levels were further explored in 10,282 participants from the DFTJ-cohort.
Briefly, we identified two previously reported UA loci of SLC2A9 (rs11722228, combined P = 8.98 × 10-31) and ABCG2 (rs2231142, combined P = 3.34 × 10-42). The two independent SNPs rs11722228 and rs2231142 explained 1.03% and 1.09% of the total variation of UA levels, respectively. Heterogeneity was observed across different populations. More importantly, both independent SNPs rs11722228 and rs2231142 were nominally significantly interacted with gender on serum UA levels (P for interaction = 4.0 × 10-2 and 2.0 × 10-2, respectively). The minor allele (T) for rs11722228 in SLC2A9 has greater influence in elevating serum UA levels in females compared to males and the minor allele (T) of rs2231142 in ABCG2 had stronger effects on serum UA levels in males than that in females.
Two genetic loci (SLC2A9 and ABCG2) were confirmed to be associated with serum UA concentration. These findings strongly support the evidence that SLC2A9 and ABCG2 function in UA metabolism across human populations. Furthermore, we observed these associations are modified by gender.
PMCID: PMC3923000  PMID: 24513273
Genome-wide association study; Serum uric acid; Ethnic differences; Gene-environment interaction
13.  Serum Omentin-1 as a Disease Activity Marker for Crohn's Disease 
Disease Markers  2014;2014:162517.
Background and Aim. It remains challenging to determine the inflammatory activity in Crohn's disease (CD) for lack of specific laboratory markers. Recent studies suggest that serum omentin-1 is associated with inflammatory response. We aimed to assess the potential of serum omentin-1 as a marker of disease activity in CD patients. Methods. Serum omentin-1 concentrations were determined by enzyme-linked immunosorbent assay (ELISA) in patients with CD (n = 240), functional gastrointestinal disorders (FGDs, n = 120), and healthy controls (HC, n = 60) and evaluated for correlation with disease activity. Expression of omentin-1 in colonic tissues from patients with CD was also analyzed by real-time PCR and Western blotting. Serum omentin-1 levels as an activity index were evaluated using a receiver operating characteristic (ROC) curve. Results. Serum omentin-1 concentrations were significantly decreased in active CD patients compared with patients in remission, FGDs, and HC (all P < 0.001). Expression of omentin-1 was decreased at mRNA and protein levels in inflamed colonic tissues in active CD than that in noninflamed colonic tissues. Serum omentin-1 levels were negatively correlated with disease activity in CD, better than C-reactive protein (CRP). Conclusion. Our results indicate that serum and colonic omentin-1 expressions are decreased in active CD patients. The correlation of serum omentin-1 with disease activity in CD is superior to that of CRP. Serum omentin-1 is a potential marker for CD disease activity.
PMCID: PMC3934650  PMID: 24659847
14.  Temozolomide for treatment of brain metastases: A review of 21 clinical trials 
Brain metastases from solid tumours are associated with poor prognosis despite aggressive treatment. Temozolomide can be used for the treatment of glioblastoma multiforme as well as melanoma. It has also been shown to have activity in patients with brain metastases from various malignancies, since it can cross the blood-brain barrier. To better understand the efficacy of temozolomide in the treatment of brain metastases, we carried out a review of 21 published clinical trials to determine whether temozolomide would benefit patients with brain metastases from solid tumours. Information regarding complete response, partial response, stable disease, objective response and objective response rate were collected to assess clinical outcomes. A modest therapeutic effect was observed when temozolomide was used as a single agent, however, the combination of temozolomide with whole-brain radiotherapy and/or other anticancer drugs exhibited encouraging activity. Thus, future high quality studies are warranted to confirm our findings.
PMCID: PMC3920177  PMID: 24527399
Temozolomide; Solid tumours; Brain metastases; Clinical trials; Clinical outcomes
15.  Deletion of microRNA miR-223 increases Langerhans cell cross-presentation 
Langerhans cells (LCs) are skin-residential dendritic cells that regulate skin immunity. MicroRNAs (miRNAs) are key regulators in the control of biological functions in a variety of cell types. Deletion of all miRNAs interrupts the homeostasis and function of epidermal LCs. However, the roles of individual miRNAs in regulating LC development and function are still completely unknown. MiRNA miR-233 is especially expressed in the myeloid compartment. Here, we reported that miR-223 is highly expressed in freshly isolated epidermal LCs, and tested whether miR-223 regulates LC development and function using miR-223 knockout (KO) mice. We found that the number, maturation, migration and phagocytic capacity of LCs were comparable between miR-223KO and wild-type mice. However, lack of miR-223 significantly increases LCs-mediated antigen-specific CD8+ T cell proliferation in vivo and in vitro, while LCs from KO and WT mice showed comparable stimulation for antigen-specific CD4+ T cells. Our data suggest that miR-223 negatively regulates LC cross-presentation, but may not be required for normal LC homeostasis and development.
PMCID: PMC3757948  PMID: 23153510
Langerhans cells; microRNA; miR-223; cross-presentation
16.  Patterns of Lymph Node Recurrence after Radical Surgery Impacting on Survival of Patients with pT1-3N0M0 Thoracic Esophageal Squamous Cell Carcinoma 
Journal of Korean Medical Science  2014;29(2):217-223.
The aim of this study was to investigate how patterns of lymph nodes recurrence after radical surgery impact on survival of patients with pT1-3N0M0 thoracic esophageal squamous cell carcinoma. One hundred eighty consecutive patients with thoracic esophageal squamous cell carcinoma underwent radical surgery, and the tumors were staged as pT1-3N0M0 by postoperative pathology. Lymph nodes recurrence was detected with computed tomography 3-120 months after the treatment. The patterns of lymph nodes recurrence including stations, fields and locations of recurrent lymph nodes, and impacts on patterns of survival were statistically analyzed. There was a decreasing trend of overall survival with increasing stations or fields of postoperative lymph nodes involved (all P<0.05). Univariate analysis showed that stations or fields of lymph nodes recurrence, and abdominal or cervical lymph nodes involved were prognostic factors for survival (all P<0.05). Cox analyses revealed that the field was an independent factor (P<0.05, odds ratio=2.73). Lymph nodes involved occurred predominantly in cervix and upper mediastinum (P<0.05). In conclusion, patterns of lymph node recurrence especially the fields of lymph nodes involved are significant prognostic factors for survival of patients with pT1-3N0M0 thoracic esophageal squamous cell carcinoma.
PMCID: PMC3924000  PMID: 24550648
Esophageal Squamous Cell Carcinoma; Thorax; Lymph Node Recurrence; Tomography, X-Ray Computed; Radical Esophagectomy
17.  Compound danshen tablet ameliorated aβ25-35-induced spatial memory impairment in mice via rescuing imbalance between cytokines and neurotrophins 
Compound Danshen Tablet (CDT), a Traditional Chinese Medicine, has recently been reported to improve spatial cognition in a rat model of Alzheimer’s disease. However, in vivo neuroprotective mechanism of the CDT in models of spatial memory impairment is not yet evaluated. The present study is aimed to elucidate the cellular mechanism of CDT on Aβ25-35-induced cognitive impairment in mice.
Mice were randomly divided into 5 groups: the control group (sham operated), the Aβ25-35 treated group, the positive drug group, and large and small dosage of the CDT groups, respectively. CDT was administered at a dose of 0.81 g/kg and 0.405 g/kg for 3 weeks. The mice in the positive drug group were treated with 0.4 mg/kg of Huperzine A, whereas the mice of the control and Aβ25-35 treated groups were administrated orally with equivalent saline. After 7 days of preventive treatment, mice were subjected to lateral ventricle injection of Aβ25-35 to establish the mice model of Alzheimer’s disease. Spatial memory impairment was evaluated by Morris water maze test. Choline acetyltransferase (ChAT) contents in hippocampus and cortex were quantified by ELISA. The levels of cytokines, receptor of activated protein kinase C1 (RACK1) and brain-derived neurotrophic factor (BDNF) in hippocampus were measured by RT-PCR and ELISA.
The results showed that Aβ25-35 caused spatial memory impairment as demonstrated by performance in the Morris water maze test. CDT was able to confer a significant improvement in spatial memory, and protect mice from Aβ25-35-induced neurotoxicity. Additionally, CDT also inhibited the increase of TNF-α and IL-6 level, and increased the expression of choline acetyltransferase (ChAT), receptor of activated protein kinase C1 (RACK1) and brain-derived neurotrophic factor (BDNF) in brain as compared to model mice.
These findings strongly implicate that CDT may be a useful treatment against learning and memory deficits in mice by rescuing imbalance between cytokines and neurotrophins.
PMCID: PMC3898400  PMID: 24422705
Compound danshen tablet; Spatial memory impairment; ChAT; RACK1; BDNF
18.  Packaging and Non-Hermetic Encapsulation Technology for Flip Chip on Implantable MEMS Devices 
We report here a successful demonstration of a flip-chip packaging approach for a microelectromechanical systems (MEMS) device with in-plane movable microelectrodes implanted in a rodent brain. The flip-chip processes were carried out using a custom-made apparatus that was capable of the following: 1) creating Ag epoxy microbumps for first-level interconnect; 2) aligning the die and the glass substrate; and 3) creating non-hermetic encapsulation (NHE). The completed flip-chip package had an assembled weight of only 0.5 g significantly less than the previously designed wire-bonded package of 4.5 g. The resistance of the Ag bumps was found to be negligible. The MEMS micro-electrodes were successfully tested for its mechanical movement with microactuators generating forces of 450 μN with a displacement resolution of 8.8 μm/step. An NHE on the front edge of the package was created by patterns of hydrophobic silicone microstructures to prevent contamination from cerebrospinal fluid while simultaneously allowing the microelectrodes to move in and out of the package boundary. The breakdown pressure of the NHE was found to be 80 cm of water, which is significantly (4.5–11 times) larger than normal human intracranial pressures. Bench top tests and in vivo tests of the MEMS flip-chip packages for up to 75 days showed reliable NHE for potential long-term implantation.
PMCID: PMC3888989  PMID: 24431925
Actuators; biomedical microelectromechanical systems (MEMS) (bio-MEMS); flip chip; hydrophobic silicone; microactuators
19.  Design and Testing of a Percutaneously Implantable Fetal Pacemaker 
We are developing a cardiac pacemaker with a small, cylindrical shape that permits percutaneous implantation into a fetus to treat complete heart block and consequent hydrops fetalis, which can otherwise be fatal. The device uses off-the-shelf components including a rechargeable lithium cell and a highly efficient relaxation oscillator encapsulated in epoxy and glass. A corkscrew electrode made from activated iridium can be screwed into the myocardium, followed by release of the pacemaker and a short, flexible lead entirely within the chest of the fetus to avoid dislodgement from fetal movement. Acute tests in adult rabbits demonstrated the range of electrical parameters required for successful pacing and the feasibility of successfully implanting the device percutaneously under ultrasonic imaging guidance. The lithium cell can be recharged inductively as needed, as indicated by a small decline in the pulsing rate.
PMCID: PMC3524376  PMID: 22855119
Cardiac pacemaker; fetus; congenital heart block; complete heart block; hydrops fetalis
20.  C1q-like Factor, a Target of miR-430, Regulates Primordial Germ Cell Development in Early Embryos of Carassius auratus 
C1q-like is a significant maternal factor of TNF/C1q super-family, and the abundant protein has been observed in both mature eggs of Carassius auratus and Carassius auratus gibelio, but its biological function in early embryo development has remained unclear. In this study, we firstly revealed a high level of maternal C1q-like transcript existence only in mature eggs of Carassius auratus, whereas no any maternal C1q-like transcript was observed in that of Carassius auratus gibelio. During embryonic development, the C1q-like zygotic expression begins around cardiopalmus stage in embryos of both Carassius auratus and Carassius auratus gibelio. Then, we examined the biological role of C1q-like by morpholino-mediated knockdown in early embryo development. Knockdown of CaOC1q resulted in a significant reduction of primordial germ cells (PGCs) in Carassius auratus, as shown by whole mount in situ hybridization with vasa-specific RNA probe, fluorescence immunostaining of vasa protein, and GFP imaging of the GFP-nanos1-3'UTR mRNA reporter. In vitro and in vivo evidence indicated that a microRNA, miR-430 could repress the C1q-like expression and PGC development. These data suggest that C1q-like should be a direct target of miR-430 and play an essential role in PGC development of Carassius auratus.
PMCID: PMC3879587  PMID: 24391447
C1q-like; microRNA; miR-430; knockdown; primordial germ cell; early embryogenesis
21.  A Genome Wide Association Study Identifies Common Variants Associated with Lipid Levels in the Chinese Population 
PLoS ONE  2013;8(12):e82420.
Plasma lipid levels are important risk factors for cardiovascular disease and are influenced by genetic and environmental factors. Recent genome wide association studies (GWAS) have identified several lipid-associated loci, but these loci have been identified primarily in European populations. In order to identify genetic markers for lipid levels in a Chinese population and analyze the heterogeneity between Europeans and Asians, especially Chinese, we performed a meta-analysis of two genome wide association studies on four common lipid traits including total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL) and high-density lipoprotein cholesterol (HDL) in a Han Chinese population totaling 3,451 healthy subjects. Replication was performed in an additional 8,830 subjects of Han Chinese ethnicity. We replicated eight loci associated with lipid levels previously reported in a European population. The loci genome wide significantly associated with TC were near DOCK7, HMGCR and ABO; those genome wide significantly associated with TG were near APOA1/C3/A4/A5 and LPL; those genome wide significantly associated with LDL were near HMGCR, ABO and TOMM40; and those genome wide significantly associated with HDL were near LPL, LIPC and CETP. In addition, an additive genotype score of eight SNPs representing the eight loci that were found to be associated with lipid levels was associated with higher TC, TG and LDL levels (P = 5.52×10-16, 1.38×10-6 and 5.59×10-9, respectively). These findings suggest the cumulative effects of multiple genetic loci on plasma lipid levels. Comparisons with previous GWAS of lipids highlight heterogeneity in allele frequency and in effect size for some loci between Chinese and European populations. The results from our GWAS provided comprehensive and convincing evidence of the genetic determinants of plasma lipid levels in a Chinese population.
PMCID: PMC3875415  PMID: 24386095
22.  PPARγ Agonist Rosiglitazone Suppresses Renal mPGES-1/PGE2 Pathway in db/db Mice 
PPAR Research  2013;2013:612971.
Evidence had shown the detrimental effect of prostaglandin (PG) E2 in diabetic nephropathy (DN) of STZ-induced type-1 diabetes but its role in the development of DN of type-2 diabetes remains uncertain. The present study was undertaken to investigate the regulation of PGE2 synthetic pathway and the interaction between peroxisome proliferator-activated receptor (PPAR)γ and PGE2 synthesis in the kidneys of db/db mice. Strikingly, urinary PGE2 was remarkably elevated in db/db mice paralleled with the increased protein expressions of COX-2 and mPGES-1. In contrast, the protein expressions of COX-1, mPGES-2, cPGES, and 15-hydroxyprostaglandin dehydrogenase (15-PGDH) were not altered. Following 1-week rosiglitazone (Rosi) therapy, urinary PGE2, but not other prostanoids, was reduced by 57% in parallel with significant reduction of mPGES-1 protein and EP4 mRNA expressions. By immunohistochemistry, mPGES-1 was significantly induced in the glomeruli of db/db mice, which was almost entirely abolished by Rosi. In line with the reduction of glomerular mPGES-1, the glomerular injury score showed a tendency of improvement after 1 week of Rosi therapy. Collectively, the present study demonstrated an inhibitory effect of PPARγ activation on renal mPGES-1/PGE2/EP4 pathway in type-2 diabetes and suggested that mPGES-1 may potentially serve as a therapeutic target for treating type-2 diabetes-associated DN.
PMCID: PMC3892750  PMID: 24489534
23.  Optimal Duration of Fluorouracil-Based Adjuvant Chemotherapy for Patients with Resectable Gastric Cancer 
PLoS ONE  2013;8(12):e83196.
Although several clinical trials have suggested that postoperative adjuvant chemotherapy can improve survival of patients with gastric cancer, the optimal treatment duration has not been studied. This retrospective analysis evaluated the outcomes of patients with gastric cancer treated with six cycles of fluorouracil-based treatment compared with a cohort treated with four or eight cycles.
We retrospectively identified 237 patients with stage IB–IIIC gastric cancer who received four, six, or eight cycles of fluorouracil-based adjuvant chemotherapy administered every 3 weeks after radical gastrectomy. The endpoint was overall survival (OS). Factors associated with prognosis were also analyzed.
The estimated 3-year OS rates for the four-, six-, and eight-cycle cohorts were 54.4%, 76.1%, and 68.9%, respectively; and the estimated 5-year OS rates were 41.2%, 74.0%, and 65.8%, respectively. Patients who received six cycles were more likely to have a better OS than those who received four cycles (P = 0.002). Eight cycles failed to show an additional survival benefit (P = 0.454). In the multivariate analysis, the number of chemotherapy cycles was associated with OS independent of clinical covariates (P<0.05). Subgroup analysis suggested that among patients in all age groups examined, male patients, and subgroups of fluorouracil plus oxaliplatin combined chemotherapy, stage III, poor differentiation, and gastrectomy with D2 lymphadenectomy, six cycles of adjuvant chemotherapy were associated with a statistically significant benefit of OS compared with four cycles (P<0.05).
Six cycles of adjuvant chemotherapy might lead to a favorable outcome for patients with gastric cancer, and two further cycles could not provide an additional clinical benefit.
PMCID: PMC3873471  PMID: 24386161
24.  Oligonucleotide Microarray Identifies Genes Differentially Expressed during Tumorigenesis of DMBA-Induced Pancreatic Cancer in Rats 
PLoS ONE  2013;8(12):e82910.
The extremely dismal prognosis of pancreatic cancer (PC) is attributed, at least in part, to lack of early diagnosis. Therefore, identifying differentially expressed genes in multiple steps of tumorigenesis of PC is of great interest. In the present study, a 7,12-dimethylbenzanthraene (DMBA)-induced PC model was established in male Sprague-Dawley rats. The gene expression profile was screened using an oligonucleotide microarray, followed by real-time quantitative polymerase chain reaction (qRT-PCR) and immunohistochemical staining validation. A total of 661 differentially expressed genes were identified in stages of pancreatic carcinogenesis. According to GO classification, these genes were involved in multiple molecular pathways. Using two-way hierarchical clustering analysis, normal pancreas, acute and chronic pancreatitis, PanIN, early and advanced pancreatic cancer were completely discriminated. Furthermore, 11 upregulated and 142 downregulated genes (probes) were found by Mann-Kendall trend Monotone test, indicating homologous genes of rat and human. The qRT-PCR and immunohistochemistry analysis of CXCR7 and UBe2c, two of the identified genes, confirmed the microarray results. In human PC cell lines, knockdown of CXCR7 resulted in decreased migration and invasion. Collectively, our data identified several promising markers and therapeutic targets of PC based on a comprehensive screening and systemic validation.
PMCID: PMC3871567  PMID: 24376604
25.  Assessment of the Rotation Motion at the Papillary Muscle Short-Axis Plane with Normal Subjects by Two-Dimensional Speckle Tracking Imaging: A Basic Clinical Study 
PLoS ONE  2013;8(12):e83071.
The aim of this study was to observe the rotation patterns at the papillary muscle plane in the Left Ventricle(LV) with normal subjects using two-dimensional speckle tracking imaging(2D-STI).
We acquired standard of the basal, the papillary muscle and the apical short-axis images of the LV in 64 subjects to estimate the LV rotation motion by 2D-STI. The rotational degrees at the papillary muscle short-axis plane were measured at 15 different time points in the analysis of two heart cycles.
There were counterclockwise rotation, clockwise rotation, and counterclockwise to clockwise rotation at the papillary muscle plane in the LV with normal subjects, respectively. The ROC analysis of the rotational degrees was performed at the papillary muscle short-axis plane at the peak LV torsion for predicting whether the turnaround point of twist to untwist motion pattern was located at the papillary muscle level. Sensitivity and specificity were 97% and 67%, respectively, with a cut-off value of 0.34°, and an area under the ROC curve of 0.8. At the peak LV torsion, there was no correlation between the rotational degrees at the papillary muscle short-axis plane and the LVEF in the normal subjects(r = 0.000, p = 0.998).
In the study, we conclude that there were three rotation patterns at the papillary muscle short-axis levels, and the transition from basal clockwise rotation to apical counterclockwise rotation is located at the papillary muscle level.
PMCID: PMC3869751  PMID: 24376634

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