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1.  Reconstruction of Auto-Tissue-Engineered Lamellar Cornea by Dynamic Culture for Transplantation: A Rabbit Model 
PLoS ONE  2014;9(4):e93012.
To construct an auto-tissue-engineered lamellar cornea (ATELC) for transplantation, based on acellular porcine corneal stroma and autologous corneal limbal explants, a dynamic culture process, which composed of a submersion culture, a perfusion culture and a dynamic air-liquid interface culture, was performed using appropriate parameters. The results showed that the ATELC-Dynamic possessed histological structure and DNA content that were similar to native lamellar cornea (NLC, p>0.05). Compared to NLC, the protein contents of zonula occludens-1, desmocollin-2 and integrin β4 in ATELC-Dynamic reached 93%, 89% and 73%, respectively. The basal cells of ATELC-Dynamic showed a better differentiation phenotype (K3−, P63+, ABCG2+) compared with that of ATELC in static air-lift culture (ATELC-Static, K3+, P63−, ABCG2−). Accordingly, the cell-cloning efficiency of ATELC-Dynamic (9.72±3.5%) was significantly higher than that of ATELC-Static (2.13±1.46%, p<0.05). The levels of trans-epithelial electrical resistance, light transmittance and areal modulus variation in ATELC-Dynamic all reached those of NLC (p>0.05). Rabbit lamellar keratoplasty showed that the barrier function of ATELC-Dynamic was intact, and there were no signs of epithelial shedding or neovascularization. Furthermore, the ATELC-Dynamic group had similar optical properties and wound healing processes compared with the NLC group. Thus, the sequential dynamic culture process that was designed according to corneal physiological characteristics could successfully reconstruct an auto-lamellar cornea with favorable morphological characteristics and satisfactory physiological function.
PMCID: PMC3976280  PMID: 24705327
2.  Role of NH2-terminal fragment of Dentin Sialophosphoprotein (DSPP) in dentinogenesis 
DSPP is a large precursor protein that is proteolytically processed into three fragments: a NH2-terminal fragment [dentin sialoprotein (DSP), a proteoglycan form (DSP-PG)] and a COOH-terminal fragment [dentin phosphoprotein (DPP)]. In vitro studies indicate that DPP is a strong initiator and regulator of hydroxyapatite crystal formation and growth, but the role(s) of the NH2-terminal fragment of DSPP (i.e., DSP and DSP-PG) in dentinogenesis remain unclear. This study focuses on the function of the NH2-terminal fragment of DSPP in dentinogenesis. Here, transgenic mouse lines expressing the NH2-terminal fragment of DSPP driven by 3.6-kb type I collagen promoter (Col 1a1) were generated and crossbred with Dspp null mice to obtain mice that express the transgene but lack the endogenous Dspp (Dspp KO/DSP Tg). We found dentin from the Dspp KO/DSP Tg mice was much thinner; more poorly mineralized and remarkably disorganized compared to the Dspp KO mice. The fact that Dspp KO/DSP Tg mice exhibited more severe dentin defects than the Dspp null mice indicates that the NH2-terminal fragment of DSPP may inhibit dentin mineralization or may serve as an antagonist against the accelerating action of DPP and serve to prevent predentin from being mineralized too rapidly during dentionogenesis.
PMCID: PMC3602929  PMID: 23489896
DSPP; Proteolytic processing; Posttranslational modification; biomineralization; dentin
3.  Common genetic variants of the human UMOD gene are functional on transcription and predict plasma uric acid in two distinct populations 
Kidney international  2013;83(4):733-740.
Uromodulin (UMOD) genetic variants cause familial juvenile hyperuricemic nephropathy, characterized by hyperuricemia, decreased renal excretion of UMOD and uric acid; such findings suggest a role for UMOD in the regulation of plasma uric acid. We screened common variants across the UMOD locus in two populations, one from a community-based Chinese population, the other from California twins and siblings. Transcriptional activity of promoter variants was estimated in luciferase reporter plasmids transfected into HEK293 cells and mlMCD3 cells. By variance components in twin pairs, uric acid concentration and excretion were heritable traits. In the primary population from Beijing, we identified that carriers of haplotype GCC displayed higher plasma uric acid, and 3 UMOD promoter variants associated with plasma uric acid. UMOD promoter variants displayed reciprocal effects on urine uric acid excretion and plasma uric acid concentration, suggesting a primary effect on renal tubular handling of urate. These UMOD genetic marker-on-trait associations for uric acid were replicated in an independent American population sample. Site-directed mutagenesis at trait-associated UMOD promoter variants altered promoter activity in transfected luciferase reporter plasmids. These results suggest that UMOD promoter variants seem to initiate a cascade of transcriptional and biochemical changes influencing UMOD secretion, eventuating in elevation of plasma uric acid.
PMCID: PMC3687544  PMID: 23344472
Uromodulin; uric acid; Tamm-Horsfall protein; UMOD
5.  Identification and Characterization of a Suite of Tumor Targeting Peptides for Non-Small Cell Lung Cancer 
Scientific Reports  2014;4:4480.
Tumor targeting ligands are emerging components in cancer therapies. Widespread use of targeted therapies and molecular imaging is dependent on increasing the number of high affinity, tumor-specific ligands. Towards this goal, we biopanned three phage-displayed peptide libraries on a series of well-defined human non-small cell lung cancer (NSCLC) cell lines, isolating 11 novel peptides. The peptides show distinct binding profiles across 40 NSCLC cell lines and do not bind normal bronchial epithelial cell lines. Binding of specific peptides correlates with onco-genotypes and activation of particular pathways, such as EGFR signaling, suggesting the peptides may serve as surrogate markers. Multimerization of the peptides results in cell binding affinities between 0.0071–40 nM. The peptides home to tumors in vivo and bind to patient tumor samples. This is the first comprehensive biopanning for isolation of high affinity peptidic ligands for a single cancer type and expands the diversity of NSCLC targeting ligands.
PMCID: PMC3967199  PMID: 24670678
6.  Serum level of DKK-1 and its prognostic potential in non–small cell lung cancer 
Diagnostic Pathology  2014;9:52.
The aim of the present study was to measure the serum level of dickkopf-1(DKK-1) in patients with non-small cell lung cancer (NSCLC), and to determine the prognostic potential of serum DKK-1 in NSCLC.
Material and methods
The present study included a total of 150 patients with NSCLC and 150 healthy controls. Serum level of DKK-1 was measured by enzyme-linked immunosorbent assay (ELISA). Numerical variables were recorded as means ± standard deviation (SD) and analyzed by independent t-tests. Categorical variables were presented as rates and analyzed by using the chi-square test or Fisher’s exact test. The overall survival was analyzed by log-rank test, and survival curves were plotted according to Kaplan–Meier.
We found that serum DKK-1 level was significantly higher in patients with NSCLC than healthy controls. Mean serum DKK-1 level was 31.42 ± 6.32 ng/ml in the NSCLC group and 14.12 ± 3.29 ng/ml in the healthy control group (p <0.01). Serum DKK-1 level expression level was significantly positively correlated with TNM stage (p = 0.009), lymph node involvement(p = 0.001), and distant metastases(p < 0.001).
In the multivariate Cox proportional hazards analysis, high DKK-1 expression was independently associated with poor survival (P < 0.001; HR = 3.98; 95% CI =2.19-4.83).
In conclusion, our results showed that DKK-1 was overexpressed in NSCLC, and DKK-1 in serum was a good predictor of poor prognosis in patients with NSCLC. More researches are needed in the future to clarify the detailed mechanism of DKK-1 in the carcinogenesis and metastasis of NSCLC.
Virtual slides
The virtual slides for this article can be found here:
PMCID: PMC3975329  PMID: 24612589
Dickkopf-1; Non-small cell lung cancer; Prognosis
7.  Formylpeptide Receptors Mediate Rapid Neutrophil Mobilization to Accelerate Wound Healing 
PLoS ONE  2014;9(3):e90613.
Wound healing is a multi-phased pathophysiological process requiring chemoattractant receptor-dependent accumulation of myeloid cells in the lesion. Two G protein-coupled formylpeptide receptors Fpr1 and Fpr2 mediate rapid neutrophil infiltration in the liver of Listeria-infected mice by sensing pathogen-derived chemotactic ligands. These receptors also recognize host-derived chemotactic peptides in inflammation and injury. Here we report the capacity of Fprs to promote the healing of sterile skin wound in mice by initiating neutrophil infiltration. We found that in normal miceneutrophils rapidly infiltrated the dermis in the wound before the production of neutrophil-specific chemokines by the injured tissue. In contrast, rapid neutrophil infiltration was markedly reduced with delayed wound closure in mice deficient in both Fprs. In addition, we detected Fpr ligand activity that chemoattracted neutrophils into the wound tissue. Our study thus demonstrates that Fprs are critical for normal healing of the sterile skin wound by mediating the first wave of neutrophil infiltration.
PMCID: PMC3946181  PMID: 24603667
8.  C-MYC Controlled TIP110 Protein Expression Regulates OCT4 mRNA Splicing in Human Embryonic Stem Cells 
Stem Cells and Development  2012;22(5):689-694.
We reported previously that HIV-1 the Tat-interacting protein of 110 kDa (TIP110; P110(NRB)/SART3/p110) is important in regulation of hematopoiesis, and in maintaining pluripotent factor (NANOG, OCT4, and SOX2) expression in and pluripotency of human embryonic stem cells (hESCs). Here we show that TIP110 expression in hESCs line H9 and embryonal carcinoma cell line NT-2 is regulated by C-MYC expression in ESCs through an E box present in the TIP110 promoter region. Through up- and down- modulation of expression, TIP110 induces OCT4 exon 1a inclusion and exon 1b skipping in our OCT4 minigene model. Thus, TIP110 expression in ESCs regulates alternative splicing of OCT4, an event required for pluripotency of ESCs.
PMCID: PMC3578368  PMID: 23088399
9.  Adiponectin Corrects High-Fat Diet–Induced Disturbances in Muscle Metabolomic Profile and Whole-Body Glucose Homeostasis 
Diabetes  2013;62(3):743-752.
We provide here a detailed and comprehensive analysis of skeletal muscle metabolomic profiles in response to adiponectin in adiponectin knockout (AdKO) mice after high-fat–diet (HFD) feeding. Hyperinsulinemic-euglycemic clamp studies showed that adiponectin administration corrected HFD-induced defects in post/basal insulin stimulated Rd and insulin signaling in skeletal muscle. Lipidomic profiling of skeletal muscle from HFD-fed mice indicated elevated triacylglycerol and diacylglycerol species (16:0–18:1, 18:1, and 18:0–18:2) as well as acetyl coA, all of which were mitigated by adiponectin. HFD induced elevated levels of various ceramides, but these were not significantly altered by adiponectin. Adiponectin corrected the altered branched-chain amino acid metabolism caused by HFD and corrected increases across a range of glycerolipids, fatty acids, and various lysolipids. Adiponectin also reversed induction of the pentose phosphate pathway by HFD. Analysis of muscle mitochondrial structure indicated that adiponectin treatment corrected HFD-induced pathological changes. In summary, we show an unbiased comprehensive metabolomic profile of skeletal muscle from AdKO mice subjected to HFD with or without adiponectin and relate these to changes in whole-body glucose handling, insulin signaling, and mitochondrial structure and function. Our data revealed a key signature of relatively normalized muscle metabolism across multiple metabolic pathways with adiponectin supplementation under the HFD condition.
PMCID: PMC3581202  PMID: 23238294
10.  Behavior Identification Based on Geotagged Photo Data Set 
The Scientific World Journal  2014;2014:616030.
The popularity of mobile devices has produced a set of image data with geographic information, time information, and text description information, which is called geotagged photo data set. The division of this kind of data by its behavior and the location not only can identify the user's important location and daily behavior, but also helps users to sort the huge image data. This paper proposes a method to build an index based on multiple classification result, which can divide the data set multiple times and distribute labels to the data to build index according to the estimated probability of classification results in order to accomplish the identification of users' important location and daily behaviors. This paper collects 1400 discrete sets of data as experimental data to verify the method proposed in this paper. The result of the experiment shows that the index and actual tagging results have a high inosculation.
PMCID: PMC3956585  PMID: 24723818
11.  The Association of HMGB1 Gene with the Prognosis of HCC 
PLoS ONE  2014;9(2):e89097.
High-mobility group box 1 protein (HMGB1) is an evolutionarily ancient and critical regulator of cell death and survival. HMGB1 is a chromatin-associated nuclear protein molecule that triggers extracellular damage. The expression of HMGB1 has been reported in many types of cancers, but the role of HMGB1 in hepato cellular carcinoma (HCC) is unknown.The aim of this study was to analyze the roles of HMGB1 in HCC progression using HCC clinical samples. We also investigated the clinical outcomes of HCC samples with a special focus on HMBG1 expression. In an immunohistochemical study conducted on 208 cases of HCC, HMGB1 had high expression in 134 cases(64.4%).The HMGB1 expression level did not correlate with any clinicopathological parameters, except alpha fetoprotein (AFP) (p = 0.041) and CLIP stage (p = 0.007). However, survival analysis showed that the group with HMBG1 overexpression had a significantly shorter overall survival time than the group with a down-regulatedexpression of HMBG1 (HR = 0.568, CI (0.398, 0.811), p = 0.002). Multivariate analysis showed that HMGB1 expression was a significant and independent prognostic parameter (HR = 0.562, CI (0.388, 0.815), p = 0.002) for HCC patients. The ability of proliferation, migration and invasion of HCC cells was suppressed with the disruption of endogenous HMGB1 using small interfering RNAs. On the other hand, the ability of proliferation, migration and invasion of HCC cells was strengthened when the expression endogenous HMGB1 was enhanced using HMGB1 DNA. HMGB1 expression may be a novel and independent predictor for the prognosis of HCC patients. The overexpression of HMGB1 in HCC could be a novel, effective, and supplementary biomarker for HCC, since it plays a vital role in the progression of HCC.
PMCID: PMC3929653  PMID: 24586525
12.  Expression of dectin-1 during fungus infection in human corneal epithelial cells 
To evaluate the expression of dendritic cell-associated C-type lectin-1 (dectin-1) in human corneal epithelial (HCE) cells infected by fungus.
A total of 20 cases of healthy donor corneas were group A, and 20 patients (20 eyes) suffered from fungal keratitis (FK) composed group B. Real-time qPCR and immunohistochemistry were applied to detect dectin-1 expression in corneal epithelium of both groups. HCE cells were cultured with aspergillus fumigatus (AF) antigens in vitro. The expression of dectin-1 mRNA was measured by real-time qPCR at the stimulation of 0, 4, 8 and 24h separately. Dectin-1 protein was detected by immunocytochemistry at 0 and 24h separately.
Dectin-1 expressed in corneal epithelium of normal persons and FK patients. Vitro cellular experiment showed that the expression of dectin-1 mRNA in HCE cells began to increase after stimulation of AF antigens at 4h, and dectin-1 protein expression increased after stimulation at 24h.
Dectin-1 expressed in corneal epithelium of normal persons. AF antigens stimulation can elevate the expression of dectin-1 in HCE cells in vitro.
PMCID: PMC3949455  PMID: 24634860
dectin-1; corneal epithelial cells; fungal keratitis; human
13.  Identification of sample donor by 24-plex short tandem repeat in a post-race equine plasma containing dexamethasone 
SpringerPlus  2014;3:94.
Animal sport such as horseracing is tainted with drug abuse as are human sports. Treatment of racehorses on race day with therapeutic medications in most cases is banned, and thus, it is essential to monitor the illicit use of drugs in the racing horse to maintain integrity of racing, ensure fair competition and protect the health, safety and welfare of the horse, jockeys and drivers. In the event of a dispute over the identity of the sample donor, if the regulator can provide evidence that the DNA genotype profile of the post-race sample matched that of the alleged donor, then the potential drug violation case might be easily resolved without legal challenges.
Case description
We present a case study of a racehorse sample that tested positive for dexamethasone in a post-race plasma sample in Pennsylvania (PA) but the result was challenged by the trainer of the horse. Dexamethasone is a synthetic glucocorticoid widely used in the management of musculoskeletal problems in horses but its presence in the horse during competition is banned by the PA Racing Commissions. The presence of dexamethasone in the post-competition plasma sample was confirmed using liquid chromatography-tandem mass spectrometry. However, this finding was challenged by the trainer of the horse alleging that the post-race sample was not collected from his/her horse and thus petitioned the Commission to be absolved of any wrong-doing. To resolve the dispute, a DNA test was ordered by the PA Racing Commission to identify the correct donor of the dexamethasone positive sample. For this purpose, a 24-plex short tandem repeat analysis to detect 21 equine markers and three human markers was employed. The results indicated that all the samples tested had identical DNA profiles and thus, it was concluded that the samples were collected from the same horse and that the probability of drawing a false conclusion was approximately zero (1.5 × 10-15).
The plasma sample confirmed for the presence of dexamethasone was collected from the alleged horse.
PMCID: PMC3935034  PMID: 24600547
Horse; Short tandem repeat; Plasma; Hair; Urine; Dexamethasone; Liquid chromatography tandem mass spectrometry
14.  MiR-141 Suppresses the Migration and Invasion of HCC Cells by Targeting Tiam1 
PLoS ONE  2014;9(2):e88393.
We have demonstrated that T lymphoma invasion and metastasis 1 (Tiam1) gene is associated with the poor prognosis of patients with hepatocellular carcinoma (HCC), and we used a computational approach to identify miR-141 as a Tiam1-targeting microRNA (miRNA). Here, we explored the function of miR-141 and the relationship between miR-141 and Tiam1 gene in HCC.
The miR-141 expression in HCC tissues and cell lines was detected and its roles in regulation of HCC cell proliferation, migration and invasion and target gene expression was investigated. Tiam1 was identified as a novel target of miR-141. Ethics statement: our study was approved by the Nanfang Hospital Medical Ethics Committee Ethics statement. Written informed consent was obtained before collection.
Based on in situ hybridization (ISH) analysis, miR-141 was down-regulated in the same HCC samples. Kaplan-Meier analysis demonstrated that patients with low miR-141 expression had poorer overall survival rate than that of the patients with high miR-141 expression. Furthermore, multivariate Cox regression analysis indicated that miR-141 could serve as an independent prognostic factor in HCC. MiR-141 significantly inhibited in vitro cell proliferation, migration and invasion as proved by gain- and loss- of function studies, while the mRNA and protein levels of Tiam1 were reduced in cells over-expressing miR-141. Moreover, Tiam1 treatment antagonized this effect, while knockdown of Tiam1 by Tiam1 short hairpin RNA (shTiam1) induced inhibitory effects.
These findings indicated that miR-141 functions as a tumor suppressor and inhibits the migration and invasion of HCC cells by targeting Tiam1, which may provide novel prognostic and treatment strategies for HCC patients.
PMCID: PMC3923786  PMID: 24551096
15.  A Comparative Study on Improved Arrhenius-Type and Artificial Neural Network Models to Predict High-Temperature Flow Behaviors in 20MnNiMo Alloy 
The Scientific World Journal  2014;2014:108492.
The stress-strain data of 20MnNiMo alloy were collected from a series of hot compressions on Gleeble-1500 thermal-mechanical simulator in the temperature range of 1173∼1473 K and strain rate range of 0.01∼10 s−1. Based on the experimental data, the improved Arrhenius-type constitutive model and the artificial neural network (ANN) model were established to predict the high temperature flow stress of as-cast 20MnNiMo alloy. The accuracy and reliability of the improved Arrhenius-type model and the trained ANN model were further evaluated in terms of the correlation coefficient (R), the average absolute relative error (AARE), and the relative error (η). For the former, R and AARE were found to be 0.9954 and 5.26%, respectively, while, for the latter, 0.9997 and 1.02%, respectively. The relative errors (η) of the improved Arrhenius-type model and the ANN model were, respectively, in the range of −39.99%∼35.05% and −3.77%∼16.74%. As for the former, only 16.3% of the test data set possesses η-values within ±1%, while, as for the latter, more than 79% possesses. The results indicate that the ANN model presents a higher predictable ability than the improved Arrhenius-type constitutive model.
PMCID: PMC3943286
16.  Numerical Analysis of the Relationship between Nasal Structure and Its Function 
The Scientific World Journal  2014;2014:581975.
The functions of the nasal cavity are closely related to its structure. In this study the three-dimensional finite element models were established based on the clinical data of twenty-four volunteers to study the influence of nasal structure on nasal functions of heating the inhaled airflow. Numerical simulations mainly concerning the airflow distribution and the airflow temperature are performed. The character of airflow heating process in these models is gained from the simulation results of these nasal cavities. The parameters describing the geometry of nasal cavity, such as the surface area of nasal airway and the volume of nasal cavity, are considered to be related to the nasal function of heating the inhaled airflow. The approximate function describing the relationship between the geometric parameters of the nasal airway and the nasal functions is gotten. This study can provide a numerical platform for studying some clinical problems and will contribute to the further research on the relationship between nasal structure and nasal functions.
PMCID: PMC3933016  PMID: 24672336
17.  Are We Doing Enough to Stem the Tide of Acquired MDR-TB in Countries with High TB Burden? Results of a Mixed Method Study in Chongqing, China 
PLoS ONE  2014;9(2):e88330.
Multi-drug resistant tuberculosis (MDR-TB) represents a threat to health and development in countries with high TB burden. China’s MDR-TB prevalence rate of 6.8% is the highest in the world. Interventions to remove barriers against effective TB control, and prevention of MDR-TB are urgently needed in the country. This paper reports a cross-sectional questionnaire survey of 513 pulmonary TB (PTB) patients, and qualitative interviews of 10 healthcare workers (HCWs), and 15 PTB patients. The objective was to assess barriers against effective control of PTB and prevention of MDR-TB by elucidating the perspectives of patients and healthcare providers. Results showed that more than half of the patients experienced patient delay of over 12.5 days. A similar proportion also experienced detection delay of over 30 days, and delay in initiating treatment of over 31 days. Consulting a non-TB health facility ≥3 times before seeking care at TB dispensary was a risk factor for both detection delay [AOR (95% CI): 1.89(1.07, 3.34) and delay in initiating treatment[AOR (95% CI): 1.88 (1.06, 3.36). Results revealed poor implementation of Directly Observed Therapy (DOT), whereby treatment of 34.3% patients was never monitored by HCWs. Only 31.8% patients had ever accessed TB health education before their TB diagnosis. Qualitative data consistently disclosed long patient delay, and indicated that patient’s poor TB knowledge and socioeconomic barriers were primary reasons for patient delay. Seeking care and being treated at a non-TB hospital was an important reason for detection delay. Patient’s long work hours and low income increased risk for treatment non-adherence. Evidence-based measures to improve TB health seeking behavior, reduce patient and detection delays, improve the quality of DOT, address financial and system barriers, and increase access to TB health promotion are urgently needed to address the burgeoning prevalence of MDR-TB in China.
PMCID: PMC3914979  PMID: 24505476
18.  Worry about cancer progression and low perceived social support: Implications for quality of life among early-stage breast cancer patients 
Worry about cancer progression and perceived social support can affect cancer survivors’ quality of life (QOL).
In 480 early-stage breast cancer survivors, we examined how worry about cancer progression and perceived social support six months after definitive surgery were associated with QOL (RAND 36-item Health Survey) at six-, 12-, and 24-month follow-up.
At six months post-surgery, higher worry was associated with worse QOL for five of eight subscales. Lower social support was associated with worse QOL for four subscales. The negative effects of worry and limited social support dissipated for four subscales (worry) and two subscales (social support) by 12-month follow-up and for all subscales by 24-month follow-up. Social support at six months moderated the relationship between T2 worry and T4 emotional well-being; post-hoc tests did not clarify the nature of the interaction.
Early-stage breast cancer survivors who worry about cancer progression and/or have low social support may experience lower levels of QOL that can take several months to resolve.
PMCID: PMC3561492  PMID: 22983622
quality of life; breast cancer; social support; worry; progression
20.  Molecular Signatures of Tissue-Specific Microvascular Endothelial Cell Heterogeneity in Organ Maintenance and Regeneration 
Developmental cell  2013;26(2):10.1016/j.devcel.2013.06.017.
Microvascular endothelial cells (ECs) within different tissues are endowed with distinct but as yet unrecognized structural, phenotypic, and functional attributes. We devised EC purification, cultivation, profiling, and transplantation models that establish tissue-specific molecular libraries of ECs devoid of lymphatic ECs or parenchymal cells. These libraries identify attributes that confer ECs with their organotypic features. We show that clusters of transcription factors, angiocrine growth factors, adhesion molecules, and chemokines are expressed in unique combinations by ECs of each organ. Furthermore, ECs respond distinctly in tissue regeneration models, hepatectomy, and myeloablation. To test the data set, we developed a transplantation model that employs generic ECs differentiated from embryonic stem cells. Transplanted generic ECs engraft into regenerating tissues and acquire features of organotypic ECs. Collectively, we demonstrate the utility of informational databases of ECs toward uncovering the extravascular and intrinsic signals that define EC heterogeneity. These factors could be exploited therapeutically to engineer tissue-specific ECs for regeneration.
PMCID: PMC3873200  PMID: 23871589
21.  Childhood Sexual Abuse and the Development of Recurrent Major Depression in Chinese Women 
PLoS ONE  2014;9(1):e87569.
Our prior study in Han Chinese women has shown that women with a history of childhood sexual abuse (CSA) are at increased risk for developing major depression (MD). Would this relationship be found in our whole data set?
Three levels of CSA (non-genital, genital, and intercourse) were assessed by self-report in two groups of Han Chinese women: 6017 clinically ascertained with recurrent MD and 5983 matched controls. Diagnostic and other risk factor information was assessed at personal interview. Odds ratios (ORs) were calculated by logistic regression.
We confirmed earlier results by replicating prior analyses in 3,950 new recurrent MD cases. There were no significant differences between the two data sets. Any form of CSA was significantly associated with recurrent MD (OR 4.06, 95% confidence interval (CI) [3.19–5.24]). This association strengthened with increasing CSA severity: non-genital (OR 2.21, 95% CI 1.58–3.15), genital (OR 5.24, 95% CI 3.52–8.15) and intercourse (OR 10.65, 95% CI 5.56–23.71). Among the depressed women, those with CSA had an earlier age of onset, longer depressive episodes. Recurrent MD patients those with CSA had an increased risk for dysthymia (OR 1.60, 95%CI 1.11–2.27) and phobia (OR 1.41, 95%CI 1.09–1.80). Any form of CSA was significantly associated with suicidal ideation or attempt (OR 1.50, 95% CI 1.20–1.89) and feelings of worthlessness or guilt (OR 1.41, 95% CI 1.02–2.02). Intercourse (OR 3.47, 95%CI 1.66–8.22), use of force and threats (OR 1.95, 95%CI 1.05–3.82) and how strongly the victims were affected at the time (OR 1.39, 95%CI 1.20–1.64) were significantly associated with recurrent MD.
In Chinese women CSA is strongly associated with recurrent MD and this association increases with greater severity of CSA. Depressed women with CSA have some specific clinical traits. Some features of CSA were associated with greater likelihood of developing recurrent MD.
PMCID: PMC3906190  PMID: 24489940
22.  Profiling Genome-wide Chromatin Methylation with Engineered Posttranslation Apparatus within Living Cells 
Protein methyltransferases (PMTs) have emerged as important epigenetic regulators in myriad biological processes both in normal physiology and disease conditions. However, elucidating PMT-regulated epigenetic processes has been hampered by ambiguous knowledge about in vivo activities of individual PMTs particularly because of their overlapping but non-redundant functions. To address limitations of conventional approaches in mapping chromatin modification of specific PMTs, we have engineered the chromatin-modifying apparatus and formulated a novel technology, termed Clickable Chromatin Enrichment with parallel DNA sequencing (CliEn-seq), to probe genome-wide chromatin modification within living cells. The three-step approach of CliEn-seq involves in vivo synthesis of S-adenosyl-L-methionine (SAM) analogues from cell-permeable methionine analogues by engineered SAM synthetase (methionine adenosyltransferase or MAT), in situ chromatin modification by engineered PMTs, subsequent enrichment and sequencing of the uniquely modified chromatins. Given critical roles of the chromatin-modifying enzymes in epigenetics and structural similarity among many PMTs, we envision that the CliEn-seq technology is generally applicable in deciphering chromatin methylation events of individual PMTs in diverse biological settings.
PMCID: PMC3582175  PMID: 23244065
23.  Cell surface receptor FPR2 promotes anti-tumor host defense by limiting M2 polarization of macrophages 
Cancer research  2012;73(2):550-560.
FPR2 (Fpr2 in mouse) is a G protein-coupled receptor interacting with bacterial and host-derived chemotactic agonists. Fpr2 supports innate and adaptive immune responses as illustrated by the reduction in severity of allergic airway inflammation in Fpr2-KO mice, due to impaired trafficking of antigen presenting dendritic cells (DCs). The aim of this study is to examine the role of Fpr2 in host anti-tumor responses. We found that Fpr2-KO mice bearing subcutaneously implanted Lewis lung carcinoma (LLC) cells exhibited significantly shortened survival than normal mice due to more rapidly growing tumors. In contrast, in Fpr2-transgenic mice over-expressing Fpr2, subcutaneously implanted LLC tumors grew more slowly than those in wild type (WT) littermates. Investigation of tumor tissues revealed an increased number of macrophages associated with tumors grown in Fpr2-KO mice. Macrophages derived from Fpr2-KO mice showed a more potent chemotactic response to LLC-derived supernatant (LLC Sup), which could be neutralized by an anti-CCL2 antibody. The increased chemotaxis of Fpr2-KO mouse macrophages in response to LLC Sup was due to their higher level expression of CCR4, a chemokine receptor that also recognizes the ligand CCL2. Furthermore, macrophages from Fpr2-KO mice acquired an M2 phenotype after stimulation with LLC Sup. These results suggest that Fpr2 plays an important role in host defense against implanted LLC by sustaining macrophages in an M1 phenotype with more potent anti-tumor activities.
PMCID: PMC3549056  PMID: 23139214
Fpr2; macrophages; chemotaxis; LLC; supernatant
24.  Plasma uric acid level indicates tubular interstitial leisions at early stage of IgA nephropathy 
BMC Nephrology  2014;15:11.
Hyperuricemia appeared to be a common symptom in IgA nephropathy (IgAN), even in those with normal eGFR. IgAN was characterized by variation of pathological features, especially variable tubulointerstitial lesions. Since tubular reabsorption and excretion appeared to be more important in determination of plasma uric acid levels in persons without obvious decrease of glomerular filtration rate, we took advantage of our IgAN cohort to investigate whether plasma uric acid level associated with tubular interstitial lesions, and could be considered as a maker for tubular interstitial lesions, especially at early stage with normal eGFR.
623 IgAN patients were involved in the present study. Morphological changes were evaluated with Oxford classification scoring system as well as Beijing classification system of IgAN. Statistical analysis was done with SPSS 13.0.
We found that plasma uric acid level associated with percentage of interstitial fibrosis/tubular atrophy. Higher plasma uric acid levels indicated higher tubulointerstitial scores, either with Oxford system (P = 0.012) or with Beijing classification system (P = 4.8*10-4) in the whole cohort. We also found that in the subgroup of 258 IgAN cases with normal baseline eGFR (eGFR > =90 ml/min/1.73 M2), higher plasma uric acid associated with more severe tubulointerstitial lesions with Beijing scoring system (P = 3.4*10-5). The risk of having more than 10% tubulointerstitial lesions in patients with hyperuricemia increased 58% compared with normal uric acid level. In subgroup with normal eGFR, only hyperuricemia predicted tubulointerstitial leisions, and the risk of having more tubulointerstitial changes increased 100%. Among these patients, hyperuricemia was associated with more tubulointerstitial lesions with a specificity of 60.3%. Specificity increased to 65% among those patients with eGFR > =90 ml/min/1.73 m2.
Plasma uric acid levels indicate tubular interstitial lesions in IgAN and hyperuricemia may be considered as a marker for tubulointerstitial lesions.
PMCID: PMC3898392  PMID: 24423013
IgA nephropathy; Plasma uric acid levels; Tubulointerstitial lesions
25.  ERCP for patients who have undergone Billroth II gastroenterostomy and Braun anastomosis 
Endoscopic retrograde cholangiopancreatography (ERCP) is efficacious in patients who have undergone Billroth II gastroenterostomies, but the success rate decreases in patients who also have experienced Braun anastomoses. There are currently no reports describing the preferred enterography route for cannulation in these patients. We first review the patient’s previous surgery records, which most often indicate that the efferent loop is at the greater curvature of the stomach. We recommend extending the duodenoscope along the greater curvature of the stomach and then advancing it through the “lower entrance” at the site of the gastrojejunal anastomosis, along the efferent loop, and through the “middle entrance” at the site of the Braun anastomosis to reach the papilla of Vater. Ten patients who had each undergone Billroth II gastroenterostomy and Braun anastomosis between January 2009 and December 2011 were included in our study. The overall success rate of enterography was 90% for the patients who had undergone Billroth II gastroenterostomy and Braun anastomosis, and the therapeutic success rate was 80%. We believe that this enterography route for ERCP is optimal for a patient who has had Billroth II gastroenterostomy and Braun anastomosis and helps to increase the success rate of the procedure.
PMCID: PMC3923039  PMID: 24574733
Optimal enterography route; Endoscopic retrograde cholangiopancreatography; Billroth II; Gastroenterostomy; Braun anastomosis

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