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1.  Interleukin-22 ameliorates liver fibrogenesis by attenuating hepatic stellate cell activation and downregulating the levels of inflammatory cytokines 
AIM: To investigate the effect of interleukin (IL)-22 on hepatic fibrosis in mice and the possible mechanism involved.
METHODS: Liver fibrosis was induced in male BALB/c mice by CCl4. Recombinant IL-22 (rmIL-22) was administered intraperitoneally in CCl4-treated mice. Fibrosis was assessed by histology and Masson staining. The activation of hepatic stellate cells (HSCs) was investigated by analysis of α-smooth muscle actin expression. The frequencies of T helper (Th) 22 cells, Th17 cells and Th1 cells, the expression of inflammatory cytokines [IL-22, IL-17A, interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), IL-6, IL-1β] and transcription factors [aryl hydrocarbon receptor (AHR), RAR-related orphan receptor (RORγt), T-bet] mRNA in the liver were investigated. In addition, the plasma levels of IL-22, IL-17A, IFN-γ, TNF-α, IL-6 and IL-1β were evaluated.
RESULTS: Significant elevations in circulating Th22 cells, Th17 cells, Th1 cells, IL-22, IL-17A, and IFN-γ were observed in the hepatic fibrosis group compared with the control group (P < 0.01). Treatment with rmIL-22 in mice with hepatic fibrosis ameliorated the severity of hepatic fibrosis, which was confirmed by lower hepatic fibrosis pathological scores (P < 0.01). RmIL-22 decreased the frequencies of Th22 cells (6.71% ± 0.97% vs 8.09% ± 0.74%, P < 0.01), Th17 cells (4.34% ± 0.37% vs 5.71% ± 0.24%, P < 0.01), Th1 cells (3.09% ± 0.49% vs 4.91% ± 0.73%, P < 0.01), and the levels of IL-22 (56.23 ± 3.08 vs 70.29 ± 3.01, P < 0.01), IL-17A (30.74 ± 2.77 vs 45.68 ± 2.71, P < 0.01), and IFN-γ (74.78 ± 2.61 vs 124.89 ± 2.82, P < 0.01). Down-regulation of IL-22, IL-17A, IFN-γ, TNF-α, IL-6, IL-1β, AHR RORγt, and T-bet gene expression in the liver was observed in the rmIL-22 group (P < 0.01).
CONCLUSION: The frequencies of Th22, Th17 and Th1 cells are elevated in hepatic fibrosis. RmIL-22 can attenuate HSC activation and down-regulate the levels of inflammatory cytokines, thereby ameliorating liver fibrogenesis.
PMCID: PMC4316095  PMID: 25663772
T helper 22 cells; T helper 17 cells; T helper 1 cells; Interleukin-22; Hepatic fibrosis
2.  A framework for feature extraction from hospital medical data with applications in risk prediction 
BMC Bioinformatics  2014;15(1):425.
Feature engineering is a time consuming component of predictive modeling. We propose a versatile platform to automatically extract features for risk prediction, based on a pre-defined and extensible entity schema. The extraction is independent of disease type or risk prediction task. We contrast auto-extracted features to baselines generated from the Elixhauser comorbidities.
Hospital medical records was transformed to event sequences, to which filters were applied to extract feature sets capturing diversity in temporal scales and data types. The features were evaluated on a readmission prediction task, comparing with baseline feature sets generated from the Elixhauser comorbidities. The prediction model was through logistic regression with elastic net regularization. Predictions horizons of 1, 2, 3, 6, 12 months were considered for four diverse diseases: diabetes, COPD, mental disorders and pneumonia, with derivation and validation cohorts defined on non-overlapping data-collection periods.
For unplanned readmissions, auto-extracted feature set using socio-demographic information and medical records, outperformed baselines derived from the socio-demographic information and Elixhauser comorbidities, over 20 settings (5 prediction horizons over 4 diseases). In particular over 30-day prediction, the AUCs are: COPD—baseline: 0.60 (95% CI: 0.57, 0.63), auto-extracted: 0.67 (0.64, 0.70); diabetes—baseline: 0.60 (0.58, 0.63), auto-extracted: 0.67 (0.64, 0.69); mental disorders—baseline: 0.57 (0.54, 0.60), auto-extracted: 0.69 (0.64,0.70); pneumonia—baseline: 0.61 (0.59, 0.63), auto-extracted: 0.70 (0.67, 0.72).
The advantages of auto-extracted standard features from complex medical records, in a disease and task agnostic manner were demonstrated. Auto-extracted features have good predictive power over multiple time horizons. Such feature sets have potential to form the foundation of complex automated analytic tasks.
Electronic supplementary material
The online version of this article (doi:10.1186/s12859-014-0425-8) contains supplementary material, which is available to authorized users.
PMCID: PMC4310185  PMID: 25547173
Feature extraction; Risk prediction; Hospital data
3.  A versatile platform to analyze low affinity and transient protein-protein interactions in living cells in real time 
Cell reports  2014;9(5):1946-1958.
Protein-protein interactions (PPIs) play central roles in orchestrating biological processes. While some PPIs are stable, many important ones are transient and hard to detect with conventional approaches. We developed ReBiL, a recombinase enhanced bimolecular luciferase complementation platform, to enable weak PPI detection in living cells. ReBiL readily identified challenging transient interactions between an E3 ubiquitin ligase and an E2 ubiquitin-conjugating enzyme. ReBiL’s ability to rapidly interrogate PPIs in diverse conditions revealed that some stapled α-helical peptides, a new class of PPI antagonists, induce target-independent cytosolic leakage and cytotoxicity that is antagonized by serum. These results explain the requirement for serum-free conditions to detect stapled peptide activity, and define a required parameter to evaluate for peptide antagonist approaches. ReBiL’s ability to expedite PPI analysis, assess target specificity and cell permeability, and to reveal off-target effects of PPI modifiers should facilitate development of effective, cell permeable PPI therapeutics and elaboration of diverse biological mechanisms.
PMCID: PMC4269221  PMID: 25464845
P53; Mdm2; Mdm4; Ube2t; FANCL; Bimolecular luciferase complementation; BiLC; Protein-fragment complementation assay; PCA; Recombinase mediated cassette exchange; RMCE; Protein-protein interaction; PPI; Recombinase enhanced BiLC; ReBiL; Stapled peptide; Nutlin-3a
4.  Genome-Wide Quantitative Trait Locus Mapping Identifies Multiple Major Loci for Brittle Rachis and Threshability in Tibetan Semi-Wild Wheat (Triticum aestivum ssp. tibetanum Shao) 
PLoS ONE  2014;9(12):e114066.
Tibetan semi-wild wheat (Triticum aestivum ssp. tibetanum Shao) is a semi-wild hexaploid wheat resource that is only naturally distributed in the Qinghai-Tibet Plateau. Brittle rachis and hard threshing are two important characters of Tibetan semi-wild wheat. A whole-genome linkage map of T. aestivum ssp. tibetanum was constructed using a recombinant inbred line population (Q1028×ZM9023) with 186 lines, 564 diversity array technology markers, and 117 simple sequence repeat markers. Phenotypic data on brittle rachis and threshability, as two quantitative traits, were evaluated on the basis of the number of average spike rachis fragments per spike and percent threshability in 2012 and 2013, respectively. Quantitative trait locus (QTL) mapping performed using inclusive composite interval mapping analysis clearly identified four QTLs for brittle rachis and three QTLs for threshability. However, three loci on 2DS, 2DL, and 5AL showed pleiotropism for brittle rachis and threshability; they respectively explained 5.3%, 18.6%, and 18.6% of phenotypic variation for brittle rachis and 17.4%, 13.2%, and 35.2% of phenotypic variation for threshability. A locus on 3DS showed an independent effect on brittle rachis, which explained 38.7% of the phenotypic variation. The loci on 2DS and 3DS probably represented the effect of Tg and Br1, respectively. The locus on 5AL was in very close proximity to the Q gene, but was different from the predicted q in Tibetan semi-wild wheat. To our knowledge, the locus on 2DL has never been reported in common wheat but was prominent in T. aestivum ssp. tibetanum accession Q1028. It remarkably interacted with the locus on 5AL to affect brittle rachis. Several major loci for brittle rachis and threshability were identified in Tibetan semi-wild wheat, improving the understanding of these two characters and suggesting the occurrence of special evolution in Tibetan semi-wild wheat.
PMCID: PMC4256410  PMID: 25474652
5.  Subcellular location and photodynamic therapeutic effect of chlorin e6 in the human tongue squamous cell cancer Tca8113 cell line 
Oncology Letters  2014;9(2):551-556.
The present study aimed to investigate the distribution and photodynamic therapeutic effect of chlorin e6 (Ce6) in the human tongue squamous cell carcinoma Tca8113 cell line in vitro. The distribution of Ce6 in the Tca8113 cells was observed in situ combined with mitochondrial and lysosomal fluorescent probes. Next, 630-nm semiconductor laser irradiation was performed. The MTS colorimetric method was used to determine cell survival. Annexin V fluorescein isothiocyanate/propidium iodide (PI) double staining was used to detect early apoptosis following photodynamic therapy (PDT). The flow cytometer was used to analyze the DNA content subsequent to PI-staining. It was observed that Ce6 could combine with the cellular membrane following 30 min of incubation with the Tca8113 cells. As the length of incubation increased, Ce6 gradually entered the cells in a particular distribution and reached saturation by 3 h. Co-localization analysis demonstrated that Ce6 was more likely to be present in the mitochondria than in the lysosomes. The cells incubated with 5 μg/ml Ce6 for 24 h exhibited a low toxicity of 5%, however, following light irradiation, Ce6-PDT was able to kill the Tca8113 cells in vitro. The cell toxicity was positively correlated with Ce6 concentration and light dose, therefore, the effect of Ce6 was concentration/dose-dependent (P<0.01). The lower Ce6 concentrations and light doses could significantly induce apoptosis in the Tca8113 cells, while higher doses increased necrosis/percentage of dead cells. In summary, Ce6 saturated the Tca8113 cells following 3 h of incubation. Furthermore, Ce6-PDT effectively killed the cultured Tca8113 cells in vitro at a safe concentration. At a low concentration and light dose, Ce6 is more likely to induce cell apoptosis via the mitochondria than the lysosomes.
PMCID: PMC4301477  PMID: 25621023
photodynamic therapy; chlorin; mitochondria; human tongue squamous cell carcinoma; cell death
6.  Unusual primary osseous Hodgkin’s lymphoma: A case report 
Oncology Letters  2014;9(2):677-680.
Hodgkin’s lymphoma (HL) is one of the few adult malignancies that most frequently presents with a progressive, painless enlargement of the peripheral lymph nodes. A primary osseous presentation of HL, without lymph node involvement, is extremely rare. The present study describes a case of primary multifocal osseous HL in a 22-year-old female. The patient presented with pain in the lumbar-sacral-pelvic area and a prolonged fever. Pathological examination led to a diagnosis of primary multifocal osseous lymphoma, and the patient was subsequently prescribed a course of Adriamycin, bleomycin, vinblastine and dacarbazine (ABVD) chemotherapy. Following this, the patient recovered with no pain or fever, and computed tomography identified no further progression. The clinical, radiological and histological features of HL are similar to those of other medical conditions, such as tuberculosis and eosinophilic granuloma. Furthermore, in rare cases, HL may even occur in combination with multiple myeloma. This makes it difficult to diagnose the condition, which often leads to a delay in treatment. Clinicians should not ignore HL when it manifests in the unusual primary osseous form.
PMCID: PMC4301495  PMID: 25621037
Hodgkin’s lymphoma; bone; diagnosis
7.  Changes of TCR repertoire diversity in colorectal cancer after Erbitux (cetuximab) in combination with chemotherapy 
We have previous found a positive correlation between post-therapy TCR repertoire normalization and remission of colorectal cancer (CRC) patients following fluorouracil, leucovorin, and irinotecan (FOLFIRI) plus bevacizumab or Rh-endostatin therapy. To further define the TCR repertoire diversity changes following treatment in CRC patients, and confirm its potential prognostic value, the present study extended the sample size of follow-up and used an alternative therapy regime to investigate changes of TCR repertoires following Erbitux plus FOLFIRI therapy. Inclusion and exclusion criteria have been established to screen out 26 patients to receive Erbitux plus FOLFIRI therapy. Efficacy and toxicity assessment have been made for them after 3 months’ treatment as well as the TCR repertoire diversity has been determined. A CDR3 complex scoring system was used to quantify the diversity of TCR repertoire. The results showing that the diversity of CD4+ T cells in PR group was significantly higher than that of SD and PD groups, and the difference was enlargement after treatment. The diversity of CD8+ T cells in PR group has no difference before and after treatment, but significant decrease in SD and PD group after treatment. In conclusion, analysis the diversity of T cell repertoire has an important prognosis value for CRC patients.
PMCID: PMC4266724  PMID: 25520880
Colorectal cancer (CRC); T cell receptor (TCR); TCR repertoire; complementarity determining region 3 (CDR3); Erbitux
8.  Reduced tumorigenicity and drug resistance through the downregulation of octamer-binding protein 4 and Nanog transcriptional factor expression in human breast stem cells 
Molecular Medicine Reports  2014;11(3):1647-1654.
Breast cancer is the most common type of malignancy among females. Previous studies examining breast cancer tissue have demonstrated the presence of stem cells, and have detected octamer-binding protein 4 (Oct4) and Nanog transcription factor expression. In the present study, breast cancer stem cells (CSCs) were isolated and enriched from MDA-MB-231 breast cancer cell lines, and were defined as MDA-MB-231 stem cells using flow cytometry. The expression of Oct4 and Nanog in breast CSCs were detected by quantitative polymerase chain reaction and western blotting. RNA interference (RNAi) was used in order to downregulate the expression of Oct4 and Nanog. Drug resistance and tumor-initiating capability following in vivo injection of MDA-MB-231 stem cells transduced with negative RNAi, Oct4 RNAi and Nanog RNAi were compared with that of MDA-MB-231 stem cells without siRNA transfection as a control group. In addition the capability of MDA-MB-231 breast cancer cells to initiate tumor formation in mice was compared with that of MDA-MB-231 stem cells. A paclitaxel inhibition test was also conducted in order to detect resistance of MDA-MB-231 breast cancer stem cells to this treatment. The MDA-MB-231 stem cells were revealed to exhibit elevated percentages of the cluster of differentiation (CD)44+CD24−/low subset, high tumorigenicity and resistance to chemotherapy, all of which are characteristic stem cell properties. In addition, the MDA-MB-231 stem cells were more tumorigenic in vivo. Furthermore, the breast CSCs also expressed high levels of the Oct4 and Nanog transcription factors. Therefore, downregulation of Oct4 or Nanog expression may reduce chemotherapeutic drug resistance and tumorigenicity in breast CSCs. In conclusion, Oct4 and Nanog expression may be a key factor in the development of resistance to chemotherapy and tumor growth of breast CSCs. This finding indicates that Oct4 or Nanog-targeted therapy may be a promising means of overcoming resistance to chemotherapy and inhibiting tumor growth in breast cancer treatment.
PMCID: PMC4270319  PMID: 25405855
breast cancer stem cells; isolation and identification; octamer-binding protein 4; Nanog; tumorigenicity; drug resistance
9.  A Novel Contrast-Induced Acute Kidney Injury Model Based on the 5/6-Nephrectomy Rat and Nephrotoxicological Evaluation of Iohexol and Iodixanol In Vivo 
Contrast-induced acute kidney injury (CI-AKI) is a serious complication in patients after administration of iodinated contrast media. Proper animal models of CI-AKI can help understand the mechanisms involved and prevent the disorder. We used the 5/6-nephrectomized (NE) rat to develop a CI-AKI model and to evaluate differences in the toxic effects on the kidney between iohexol and iodixanol. We found that six weeks after ablative surgery was the preferred time to induce CI-AKI. We compared multiple pretreatment plans and found that dehydration for 48 hours before iodixanol (320, 10 mL/kg) administration was optimal to induce CI-AKI in the 5/6 NE rats. Compared with iodixanol, iohexol induced a significantly greater reduction in renal function, severe renal tissue damage, intrarenal hypoxia, and apoptotic tubular cells. Iohexol and iodixanol resulted in similarly marked increases in levels of inflammation and oxidative stress. In summary, the 5/6 NE rat combined with dehydration for 48 hours is a useful pretreatment to establish a novel and reliable CI-AKI model. Iohexol induced more severe CI-AKI than iodixanol in this model.
PMCID: PMC4244948  PMID: 25478060
10.  Fluorescent Imaging of Single Nanoparticles and Viruses on a Smart Phone 
ACS nano  2013;7(10):9147-9155.
Optical imaging of nanoscale objects, whether it is based on scattering or fluorescence, is a challenging task due to reduced detection signal-to-noise ratio and contrast at subwavelength dimensions. Here, we report a field-portable fluorescence microscopy platform installed on a smart phone for imaging of individual nanoparticles as well as viruses using a lightweight and compact opto-mechanical attachment to the existing camera module of the cell phone. This hand-held fluorescent imaging device utilizes (i) a compact 450 nm laser diode that creates oblique excitation on the sample plane with an incidence angle of ~75°, (ii) a long-pass thin-film interference filter to reject the scattered excitation light, (iii) an external lens creating 2× optical magnification, and (iv) a translation stage for focus adjustment. We tested the imaging performance of this smart-phone-enabled microscopy platform by detecting isolated 100 nm fluorescent particles as well as individual human cytomegaloviruses that are fluorescently labeled. The size of each detected nano-object on the cell phone platform was validated using scanning electron microscopy images of the same samples. This field-portable fluorescence microscopy attachment to the cell phone, weighing only ~186 g, could be used for specific and sensitive imaging of subwavelength objects including various bacteria and viruses and, therefore, could provide a valuable platform for the practice of nanotechnology in field settings and for conducting viral load measurements and other biomedical tests even in remote and resource-limited environments.
PMCID: PMC3951925  PMID: 24016065
cell phone microscopy; fluorescence imaging; single nanoparticle; single virus imaging
11.  Peptidylarginine Deiminase Inhibition Reduces Vascular Damage and Modulates Innate Immune Responses in Murine Models of Atherosclerosis 
Circulation research  2014;114(6):947-956.
Neutrophil extracellular trap (NET) formation promotes vascular damage, thrombosis, and activation of interferon-α-producing plasmacytoid dendritic cells in diseased arteries. Peptidylarginine deiminase inhibition is a strategy that can decrease in vivo NET formation.
To test whether peptidylarginine deiminase inhibition, a novel approach to targeting arterial disease, can reduce vascular damage and inhibit innate immune responses in murine models of atherosclerosis.
Methods and Results
Apolipoprotein-E (Apoe)−/− mice demonstrated enhanced NET formation, developed autoantibodies to NETs, and expressed high levels of interferon-α in diseased arteries. Apoe−/− mice were treated for 11 weeks with daily injections of Cl-amidine, a peptidylarginine deiminase inhibitor. Peptidylarginine deiminase inhibition blocked NET formation, reduced atherosclerotic lesion area, and delayed time to carotid artery thrombosis in a photochemical injury model. Decreases in atherosclerosis burden were accompanied by reduced recruitment of netting neutrophils and macrophages to arteries, as well as by reduced arterial interferon-α expression.
Pharmacological interventions that block NET formation can reduce atherosclerosis burden and arterial thrombosis in murine systems. These results support a role for aberrant NET formation in the pathogenesis of atherosclerosis through modulation of innate immune responses.
PMCID: PMC4185401  PMID: 24425713
atherosclerosis; immunology; interferon-α; neutrophils; protein-arginine deiminase; thrombosis
12.  The development and evaluation of a computerized diagnosis scheme for pneumoconiosis on digital chest radiographs 
To diagnose pneumoconiosis using a computer-aided diagnosis system based on digital chest radiographs.
Lung fields were first extracted by combining the traditional Otsu-threshold method with a morphological reconstruction on digital radiographs (DRs), and then subdivided into six non-overlapping regions (region (a-f)). Twenty-two wavelet-based energy texture features were calculated exclusively from each region and selected using a decision tree algorithm. A support vector machine (SVM) with a linear kernel was trained using samples with texture features to classify an individual region of a healthy subject or a pneumoconiosis patient. The final classification results were obtained by integrating these individual classifiers with the weighted voting method. All models were developed on a dataset of 85 healthy controls and 40 stage I or II pneumoconiosis patients and validated by using the bootstrap resampling with replacement method.
The areas under receiver operating characteristic curves (AUCs) of regions (c) and (f) were 0.688 and 0.563, which were worse than those of the other four regions. Region (c) and (f) were both excluded from the individual classifiers that were going to be assembled further. When built on the selected texture features, each individual SVM showed a higher diagnostic performance for the training set and the test set. The classification performance after an ensemble was 0.997 and 0.961 of the AUC value for the training and test sets, respectively. The final results were 0.974 ± 0.018 for AUC value and 0.929 ± 0.018 for accuracy.
The integrated SVM model built on the selected feature set showed the highest diagnostic performance among all individual SVM models. The model has good potential in diagnosing pneumoconiosis based on digital chest radiographs.
PMCID: PMC4271323  PMID: 25277489
Digital radiograph; Pneumoconiosis; Bootstrap resampling; Texture feature; Support vector machine
13.  Impact of Oral Health Behaviors on Dental Caries in Children with Intellectual Disabilities in Guangzhou, China 
Dental care is consistently reported as one of the primary medical needs of children with disabilities (IDC). The aim of the present study was to explore the influence of oral health behaviors on the caries experience in children with intellectual disabilities in Guangzhou, China. A cross-sectional study was carried out in 477 intellectually disabled children, 12 to 17 years old, who were randomly selected from special educational schools in Guangzhou. A self-administered parental questionnaire was used to collect data on socio-demographic characteristics and oral health behavior variables, and 450 valid questionnaires were returned. Multiple regression analysis was used to examine the factors associated with dental caries. The average age of those in the sample was 14.6 years (SD = 1.3), 68.4% of whom were male, and the caries prevalence rate was 53.5% (DMFT = 1.5 ± 2.0). The factors significantly affecting the development of dental caries in IDC included gender, the presence or absence of cerebral palsy, and the frequency of dental visits and toothbrushing. In conclusion, the presence of cerebral palsy contributed to an increase risk of caries experience in intellectually disabled children, while toothbrushing more than twice a day and routine dental visits were caries-protective factors. Oral health promotion action may lead to a reduction in dental caries levels in IDC.
PMCID: PMC4211020  PMID: 25340906
dental caries; prevalence; intellectually disabled child; oral health behavior
14.  Effect of Photofrin-mediated photocytotoxicity on a panel of human pancreatic cancer cells 
Background and objective
Pancreatic cancer is a leading cause of cancer-related deaths in men and women. Early clinical studies suggest that photodynamic therapy (PDT) might be a useful modality in the management of this deadly disease. In this study, the photocytotoxicity of Photofrin-mediated PDT on different human pancreatic cancer cells (BxPc-3, HPAF-II, Mia PaCa-2, MPanc-96, PANC-1 and PL-45) was examined.
Materials and methods
After co-incubating cancer cells with Photofrin (0—10 [H9262]g/ml) for 4 h, the cells were irradiated with 0—6 J/cm2 of 630 nm light. The effect of Photofrin PDT on the survival of cells were examined using tetrazolium-based colorimetric assay and clonogenic assay. PDT-induced apoptosis was analyzed by flow cytometry. Expressions of apoptosis-related proteins were determined by western blot analysis.
Photofrin PDT strongly inhibited the survival of pancreatic cancer cells. A small portion of cells (<15%) underwent apoptosis 24 h after PDT at LD50. Cleavage of caspase-3, caspase-8, caspase-9 and PARP after PDT were also confirmed. BxPc-3, Mia PaCa-2, MPanc-96, and PANC-1 cells were more sensitive and HPAF-II and PL-45 cells less sensitive.
Photofrin PDT can induce apoptosis and inhibit survival of human pancreatic cancer cells.
PMCID: PMC4176883  PMID: 23993850
Photofrin; Photodynamic therapy; Pancreatic cancer cells; Apoptosis
15.  ALDH1A1 overexpression is associated with the progression and prognosis in gastric cancer 
BMC Cancer  2014;14(1):705.
Aldehyde dehydrogenase 1 family member A1 (ALDH1A1) is a cancer stem cell marker, and its expression correlates with prognosis in a number of malignancies. The aim of this study is to determine the relationship of ALDH1A1 expression with clinicopathological parameters and prognosis in gastric cancer.
ALDH1A1 and matrix metallopeptidase 9 (MMP-9) was evaluated by immunohistochemistry in 216 gastric carcinoma samples. The association between expression of ALDH1A1 and MMP-9, clinicopathological parameters, and prognosis of gastric cancer was examined.
ALDH1A1 protein expression was significantly associated with depth invasion, lymph node metastasis and stage of disease (all P < 0.05). Both univariate and multivariate analyses revealed that ALDH1A1 was an independent prognostic factor for both overall survival (OS) and recurrence-free survival (RFS) (both P < 0.001). Furthermore, ALDH1A1 overexpression was associated with poor prognosis in patients subgroups stratified by tumor size, depth invasion and lymph node metastasis. Moreover, ALDH1A1 was significantly correlated with MMP-9 among 216 gastric cancer tissues (P < 0.001). Patients who had ALDH1A1 overexpression, in which tumor cells displayed high invasiveness, had poor OS and shorter RFS.
ALDH1A1 plays an important role in tumor aggressiveness and prognosis, and may act as a promising target for prognostic prediction.
PMCID: PMC4180139  PMID: 25253129
16.  Cerium; Crystal Structure and Position in The Periodic Table 
Scientific Reports  2014;4:6398.
The properties of the cerium metal have intrigued physicists and chemists for many decades. In particular a lot of attention has been directed towards its high pressure behavior, where an isostructural volume collapse (γ phase → α phase) has been observed. Two main models of the electronic aspect of this transformation have been proposed; one where the 4f electron undergoes a change from being localized into an itinerant metallic state, and one where the focus is on the interaction between the 4f electron and the conduction electrons, often referred to as the Kondo volume collapse model. However, over the years it has been repeatedly questioned whether the cerium collapse really is isostructural. Most recently, detailed experiments have been able to remove this worrisome uncertainty. Therefore the isostructural aspect of the α-γ transition has now to be seriously addressed in the theoretical modeling, something which has been very much neglected. A study of this fundamental characteristic of the cerium volume collapse is made in present paper and we show that the localized ⇌ delocalized 4f electron picture provides an adequate description of this unique behavior. This agreement makes it possible to suggest that an appropriate crossroad position for cerium in The Periodic Table.
PMCID: PMC4165975  PMID: 25227991
17.  Remote Control of Tissue Interactions via Engineered Photo-switchable Cell Surfaces 
Scientific Reports  2014;4:6313.
We report a general cell surface molecular engineering strategy via liposome fusion delivery to create a dual photo-active and bio-orthogonal cell surface for remote controlled spatial and temporal manipulation of microtissue assembly and disassembly. Cell surface tailoring of chemoselective functional groups was achieved by a liposome fusion delivery method and quantified by flow cytometry and characterized by a new cell surface lipid pull down mass spectrometry strategy. Dynamic co-culture spheroid tissue assembly in solution and co-culture tissue multilayer assembly on materials was demonstrated by an intercellular photo-oxime ligation that could be remotely cleaved and disassembled on demand. Spatial and temporal control of microtissue structures containing multiple cell types was demonstrated by the generation of patterned multilayers for controlling stem cell differentiation. Remote control of cell interactions via cell surface engineering that allows for real-time manipulation of tissue dynamics may provide tools with the scope to answer fundamental questions of cell communication and initiate new biotechnologies ranging from imaging probes to drug delivery vehicles to regenerative medicine, inexpensive bioreactor technology and tissue engineering therapies.
PMCID: PMC4159631  PMID: 25204325
18.  Heat Shock Protein 60 Overexpression Is Associated with the Progression and Prognosis in Gastric Cancer 
PLoS ONE  2014;9(9):e107507.
Heat shock protein 60 (HSP60) is a chaperonin with essential functions for cell physiology and survival, and its expression correlates with prognosis in a number of malignancies. The aim of this study is to determine the relationship of HSP60 status with clinicopathological parameters and prognosis in gastric cancer.
The levels of HSP60 and matrix metallopeptidase 9 (MMP-9) antigen was evaluated by immunohistochemistry in 223 gastric carcinoma samples. The association between HSP60 and MMP-9, clinicopathological parameters, and prognosis of gastric cancer was examined.
The level of HSP60 protein was significantly associated with depth invasion, lymph node metastasis and stage of disease (all P<0.05). Both univariate and multivariate analyses revealed that HSP60 was an independent prognostic factor for both overall survival (OS) and recurrence-free survival (RFS) (both P<0.05). Furthermore, HSP60 overexpression was associated with a poor prognosis in patients with advanced gastric cancer in different risk groups. Moreover, HSP60 was significantly correlated with MMP-9 among 223 gastric cancer tissues (P<0.001). Patients who had HSP60 overexpression, in which tumor cells displayed high invasiveness, had poor OS and shorter RFS.
HSP60 plays an important role on tumor aggressiveness and prognosis, and may act as a promising target for prognostic prediction.
PMCID: PMC4160299  PMID: 25207654
19.  MicroRNA-376a Sensitizes Cells Following DNA Damage by Downregulating MEPE Expression 
MicroRNAs (miRNAs) are a class of endogenous molecules that post-transcriptionally regulate target gene expression and play an important role in many developmental processes. Matrix extracellular phosphoglycoprotein (MEPE) is related to bone metabolism. We recently reported that MEPE protects cells from DNA damage-induced killing. The purpose of this study is to investigate whether miRNAs targeting MEPE play an important role in DNA damage response. We report in this study that miR-376a directly targets MEPE, and overexpression of miR-376a reduces the G2 arrest of the cells and sensitizes the cells to DNA damage-induced killing. These results indicate an association of MEPE gene inactivation with decreased survival after DNA damage and also provide useful information for miRNA-based drug development: a new target for sensitizing human tumor cells to radiotherapy or chemotherapy.
PMCID: PMC3741432  PMID: 23570370
DNA damage; MEPE; microRNA; target
20.  Permittivity and Performance of Dielectric Pads with Sintered Ceramic Beads in MRI: Early Experiments and Simulations at 3 T 
Passive dielectric materials have been used to improve aspects of MRI by affecting the distribution of radiofrequency electromagnetic fields. Recently, interest in such materials has increased with the number of high-field MRI sites. Here, we introduce a new material composed of sintered high-permittivity ceramic beads in deuterated water. This arrangement maintains the ability to create flexible pads for conforming to individual subjects. The properties of the material are measured and the performance of the material is compared to previously used materials in both simulation and experiment at 3 T. Results show that both permittivity of the beads and effect on signal-to-noise ratio and required transmit power in MRI are greater than those of materials consisting of ceramic powder in water. Importantly, use of beads results in both higher permittivity and lower conductivity than use of powder.
PMCID: PMC4122217  PMID: 22890908
dielectric; MRI; signal-to-noise ratio
21.  Transcription Factor Ets1, but Not the Closely Related Factor Ets2, Inhibits Antibody-Secreting Cell Differentiation 
Molecular and Cellular Biology  2014;34(3):522-532.
B cell differentiation into antibody-secreting cells (ASCs) is a tightly regulated process under the control of multiple transcription factors. One such transcription factor, Ets1, blocks the transition of B cells to ASCs via two separate activities: (i) stimulating the expression of target genes that promote B cell identity and (ii) interfering with the functional activity of the transcription factor Blimp1. Ets1 is a member of a multigene family, several members of which are expressed within the B cell lineage, including the closely related protein Ets2. In this report, we demonstrate that Ets1, but not Ets2, can block ASC formation despite the fact that Ets1 and Ets2 bind to apparently identical DNA sequence motifs and are thought to regulate overlapping sets of target genes. The DNA binding domain of Ets1 is required, but not sufficient by itself, to block ASC formation. In addition, less conserved regions within the N terminus of Ets1 play an important role in inhibiting B cell differentiation. Differences between the N termini of Ets1 and Ets2, rather than differences in the DNA binding domains, determine whether the proteins are capable of blocking ASC formation or not.
PMCID: PMC3911503  PMID: 24277931
22.  RF Field Enhancement with High Dielectric Constant (HDC) Pads in a Receive Array Coil at 3.0 T 
To investigate the use of a new high-dielectric constant (HDC) material for improving SNR and transmission efficiency for clinical MRI applications at 3T with cervical spine imaging.
Materials and Methods
Human subjects were imaged using a commercial cervical spine receive array coil on a clinical system with and without pads containing Barium Titanate beads in deuterium water placed around the neck. Numerical electromagnetic field simulations of the same configuration were also performed.
Experimental and simulated maps of transmit and receive fields showed greater efficiency for imaging the cervical spine when the pads were present. Experimental measurements showed a significant improvement in SNR with the pads present and an average input power reduction of 46%.
Use of HDC material can enhance SNR and transmission efficiency for clinical imaging of the cervical spine at 3.0 T.
PMCID: PMC3621009  PMID: 23293090
MRI; B1 field; RF field; SAR; SNR; high permittivity
23.  Factors Associated With Mortality of HIV-Positive Clients Receiving Methadone Maintenance Treatment in China 
The Journal of Infectious Diseases  2013;208(3):442-453.
Background. Little is known about mortality of opiate users attending methadone maintenance treatment (MMT) clinics. We sought to investigate mortality and its predictors among human immunodeficiency virus (HIV)–positive MMT clients.
Methods. Records of 306 786 clients enrolled in China's MMT program from 24 March 2004 to 30 April 2011 were abstracted. Mortality rates were calculated for all HIV-positive antiretroviral treatment (ART)–naive and ART-experienced clients. Risk factors were examined using stratified proportional hazard ratios (HRs).
Results. The observed mortality rate for all clients was 11.8/1000 person-years (PY, 95% confidence interval [CI], 11.5–12.1) and 57.2/1000 PY (CI, 54.9–59.4) for HIV-positive clients (n = 18 193). An increase in average methadone doses to >75 mg/day was associated with a 24% reduction in mortality (HR = 0.76, CI, .70–.82), a 48% reduction for ART-naive HIV-positive clients (HR = 0.52, CI, .42–.65), and a 47% reduction for ART-experienced HIV-positive clients (HR = 0.53, CI, .46–.62). Among ART-experienced clients, initiation of ART when the CD4+ T-cell count was >300 cells/mm3 (HR = 0.64, CI, .43–.94) was also associated with decreased risk of death.
Conclusions. We found high mortality rates among HIV-positive MMT clients, yet decreased risk of death, with earlier ART initiation and higher methadone doses. A higher daily methadone dose was associated with reduced mortality in both HIV-infected and HIV-uninfected clients, independent of ART.
PMCID: PMC3698997  PMID: 23592864
mortality; HIV; drug users; methadone maintenance treatment; China
24.  24-Hydroxylase in Cancer: Impact on Vitamin D-based Anticancer Therapeutics 
The active vitamin D hormone 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) plays a major role in regulating calcium homeostasis and bone mineralization. 1,25(OH)2D3 also modulates cellular proliferation and differentiation in a variety of cell types. 24-hydroxylase, encoded by the CYP24A1 gene, is the key enzyme which converts 1,25(OH)2D3 to less active calcitroic acid. Nearly all cell types express 24-hydroxylase, the highest activity being observed in the kidney. There is increasing evidence linking the incidence and prognosis of certain cancers to low serum 25 (OH)D3 levels and high expression of vitamin D 24-hydroxylase supporting the idea that elevated CYP24A1 expression may stimulate degradation of vitamin D metabolites including 25-(OH)D3 and 1,25(OH)2D3. The over expression of CYP24A1 in cancer cells may be a factor affecting 1,25(OH)2D3 bioavailability and anti-proliferative activity pre-clinically and clinically. The combination of 1,25(OH)2D3 with CYP24A1 inhibitors enhances 1,25(OH)2D3 mediated signaling and anti-proliferative effects and may be useful in overcoming effects of aberrant CYP24 expression.
PMCID: PMC3686893  PMID: 23059474
CYP24; 24-hydroxylase; calcitriol and anti-tumor
25.  Association between the TP53 codon 72 polymorphism and risk of oral squamous cell carcinoma in Asians: a meta-analysis 
BMC Cancer  2014;14:469.
Several epidemiological studies have previously investigated the association between the TP53 codon 72 polymorphism and oral squamous cell carcinoma (OSCC) susceptibility; however, current results are inconsistent. We therefore performed this meta-analysis to thoroughly investigate any association among Asian patients.
A comprehensive search of PubMed and Embase databases was performed up to December 2013. We only considered studies consisting of patients diagnosed with OSCC by pathological methods. Statistical analyses were performed using Review Manager (RevMan) 5.2 software and odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the association.
A total of 11 case–control studies involving 2,298 OSCC patients and 2,111 controls were included. We found no association between the TP53 codon 72 polymorphism and OSCC susceptibility [(OR = 0.77, 95% CI = 0.48–1.22) for Arg vs. Pro; (OR = 0.67, 95% CI = 0.31–1.43) ArgArg vs. ProPro; (OR = 1.14, 95% CI = 0.97–1.35) ArgPro vs. ProPro; (OR = 0.85, 95% CI = 0.53–1.34) (ArgPro + ArgArg) vs. ProPro; or (OR = 0.34, 95% CI = 0.34–1.23) for ArgArg vs. (ProPro + ArgPro)]. However, subgroup analysis demonstrated an association between the TP53 codon 72 polymorphism and human papillomavirus (HPV)-related OSCC patients. Although statistical heterogeneity was detected, there was no evidence of publication bias.
Current results suggest that the TP53 codon 72 polymorphism is not associated with OSCC in Asians without the presence of HPV infection. Further research is necessary to determine if such a relationship exists in HPV-related OSCC patients.
PMCID: PMC4094444  PMID: 24969046
TP53 rs1042522; TP53 codon 72 polymorphism; Oral squamous cell carcinoma; Human papillomavirus; Meta-analysis

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