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2.  Energy Metabolism Disorder as a Contributing Factor of Rheumatoid Arthritis: A Comparative Proteomic and Metabolomic Study 
PLoS ONE  2015;10(7):e0132695.
To explore the pathogenesis of rheumatoid arthritis (RA), the different metabolites were screened in synovial fluid by metabolomics.
Synovial fluid from 25 RA patients and 10 normal subjects were analyzed by GC/TOF MS analysis so as to give a broad overview of synovial fluid metabolites. The metabolic profiles of RA patients and normal subjects were compared using multivariate statistical analysis. Different proteins were verified by qPCR and western blot. Different metabolites were verified by colorimetric assay kit in 25 inactive RA patients, 25 active RA patients and 20 normal subjects. The influence of hypoxia-inducible factor (HIF)-1α pathway on catabolism was detected by HIF-1α knockdown.
A subset of 58 metabolites was identified, in which the concentrations of 7 metabolites related to energy metabolism were significantly different as shown by importance in the projection (VIP) (VIP≥1) and Student’s t-test (p<0.05). In the 7 metabolites, the concentration of glucose was decreased, and the concentration of lactic acid was increased in the synovial fluid of RA patients than normal subjects verified by colorimetric assay Kit. Receiver operator characteristic (ROC) analysis shows that the concentration of glucose and lactic acid in synovial fluid could be used as dependable biomarkers for the diagnosis of active RA, provided an AUC of 0.906 and 0.922. Sensitivity and specificity, which were determined by cut-off points, reached 84% and 96% in sensitivity and 95% and 85% in specificity, respectively. The verification of different proteins identified in our previous proteomic study shows that the enzymes of anaerobic catabolism were up-regulated (PFKP and LDHA), and the enzymes of aerobic oxidation and fatty acid oxidation were down-regulated (CS, DLST, PGD, ACSL4, ACADVL and HADHA) in RA patients. The expression of HIF-1α and the enzymes of aerobic oxidation and fatty acid oxidation were decreased and the enzymes of anaerobic catabolism were increased in FLS cells after HIF-1α knockdown.
It was found that enhanced anaerobic catabolism and reduced aerobic oxidation regulated by HIF pathway are newly recognized factors contributing to the progression of RA, and low glucose and high lactic acid concentration in synovial fluid may be the potential biomarker of RA.
PMCID: PMC4492520  PMID: 26147000
3.  Uterine NDRG2 expression is increased at implantation sites during early pregnancy in mice, and its down-regulation inhibits decidualization of mouse endometrial stromal cells 
N-myc down-regulated gene 2 (NDRG2) is a tumor suppressor involved in cell proliferation and differentiation. The aim of this study was to determine the uterine expression pattern of this gene during early pregnancy in mice.
Uterine NDRG2 mRNA and protein expression levels were determined by RT-PCR and Western blot analyses, respectively, during the peri-implantation period in mice. Immunohistochemical (IHC) analysis was performed to examine the spatial localization of NDRG2 expression in mouse uterine tissues. The in vitro decidualization model of mouse endometrial stromal cells (ESCs) was used to evaluate decidualization of ESCs following NDRG2 knock down by small interfering RNA (siRNA). Statistical significance was analyzed by one-way ANOVA using SPSS 19.0 software.
Uterine NDRG2 gene expression was significantly up-regulated and was predominantly localized to the secondary decidual zone on days 5 and 8 of pregnancy in mice. Its increased expression was associated with artificial decidualization as well as the activation of delayed implantation. Furthermore, uterine NDRG2 expression was induced by estrogen and progesterone treatments. The in vitro decidualization of mouse ESCs was accompanied by up-regulation of NDRG2 expression, and knock down of its expression in these cells by siRNA inhibited the decidualization process.
These results suggest that NDRG2 might play an important role in the process of decidualization during early pregnancy.
PMCID: PMC4447025  PMID: 26013399
NDRG2; Embryo implantation; Decidualization
4.  Influence of Preferred Orientation on the Electrical Conductivity of Fluorine-Doped Tin Oxide Films 
Scientific Reports  2014;4:3679.
Current development of high-performance transparent conductive oxide (TCO) films is limited with tradeoff between carrier mobility and concentration since none of them can be improved without sacrificing the other. In this study, we prepare fluorine doped tin oxide (FTO) films by chemical vapor deposition with inclusions of different additives and report that the mobility can be varied from 0.65 to 28.5 cm2 V−1 s−1 without reducing the achieved high carrier concentration of 4 × 1020 cm−3. Such an increase in mobility is shown to be clearly associated with the development of (200) preferred orientation (PO) but concurrent degradation of (110) PO in films. Thus, at a constant high carrier concentration, the electrical conductivity can be improved via carrier mobility simply by PO control. Such a one-step approach avoiding conventional post-deposition treatment is suggested for developing next-generation FTO as well as other TCO films with better than ever conductivities.
PMCID: PMC3890905  PMID: 24419455
5.  Analysis of risk factors for adjacent superior vertebral pedicle-induced facet joint violation during the minimally invasive surgery transforaminal lumbar interbody fusion: a retrospective study 
The purpose was to explore possible risk factors of facet joint violation induced by adjacent superior vertebral pedicle screw during the minimally invasive surgery transforaminal lumbar interbody fusion (MIS-TLIF).
A total of 69 patients with lumbar degenerative disease, who underwent MIS-TLIF were retrospectively reviewed. Postoperative computed tomography images were used to assess the facet joint violation. The correlation of facet joint violations with gender, age, body mass index (BMI), the adjacent superior vertebral level, fusion segment numbers, position of screw insertion, straight leg-raising test (SLRT) results, clinical diseases and renal dysfunction were analyzed by Chi-square tests and binary logistic regression analysis.
The incidence of adjacent superior facet joint violations was 25.4 %. Chi-square test showed the patients with age <60 and high BMI (≥30 kg/m2) were more prone to have facet joint violations (P = 0.007; P = 0.006). The single segment fusion presented more facet joint violations than the double segments fusion (P = 0.048). The vertebral pedicle screw implant location at L5 showed more facet joint violations compared with that at L3 and L4 (P = 0.035). No correlation was found between gender, screw implant position, SLRT results, clinical diseases and renal dysfunction and facet joint violations. Logistic regression analysis revealed that age <60 years (OR: 2.902; 95 % CI 1.227–6.864; P = 0.015) and BMI ≥30 kg/m2 (OR: 2.825; 95 % CI 1.191–6.700; P = 0.018 < 0.05) were significantly associated with facet joint violation.
These results found a high incidence of adjacent superior vertebral facet joint violation in the MIS-TLIF. Age <60 and BMI ≥30 kg/m2 might be risk factors of facet joint violation.
Evidence level: Level 4.
PMCID: PMC4581410  PMID: 26399320
MIS-TLIF; Facet joint violation; Pedicle screw; Risk factor
6.  The anti-inflammatory and antifibrotic effects of Coreopsis tinctoria Nutt on high-glucose-fat diet and streptozotocin-induced diabetic renal damage in rats 
Diabetic nephropathy is a serious complication of diabetes whose development process is associated with inflammation, renal hypertrophy, and fibrosis. Coreopsis tinctoria Nutt, traditionally used as a healthcare tea, has anti-inflammatory, anti-hyperlipidemia, and glycemic regulation activities. The aim of our study was to investigate the renal protective effect of ethyl acetate extract of C. tinctoria Nutt (AC) on high-glucose–fat diet and streptozotocin (STZ)-induced diabetic rats.
A diabetic rat model was induced by high-glucose–fat diet and intraperitoneal injection of 35 mg/kg STZ. After treatment with AC at a daily dose of 150, 300 or, 600 mg/kg for 4 weeks, metabolic and renal function parameters of serum and urine were examined. Degree of renal damage, renal proinflammatory cytokines, and fibrotic protein expression were analyzed by histopathology and immunohistochemistry. Renal AMP-activated protein kinase (AMPK) and transforming growth factor (TGF)-β1/Smad signaling pathway were determined by western blotting.
Diabetic rats showed obvious renal dysfunction, inflammation and fibrosis. However, AC significantly reduced levels of blood glucose, total cholesterol, triglyceride, blood urea nitrogen, serum creatinine and urinary albumin, as well as expression of kidney proinflammatory cytokines of monocyte chemoattractant protein-1 and intercellular adhesion molecule-1. AC also ameliorated renal hypertrophy and fibrosis by reducing fibronectin and collagen IV and suppressing the TGF-β1/Smad signaling pathway. Meanwhile, AMPKα as a protective cytokine was markedly stimulated by AC.
In summary, AC controls blood glucose, inhibits inflammatory and fibrotic processes, suppresses the TGF-β1/Smad signaling pathway, and activates phosphorylation of AMPKα in the kidneys, which confirms the protective effects of AC in the early stage of diabetic kidney disease.
PMCID: PMC4561427  PMID: 26346939
Diabetic nephropathy; Coreopsis tinctoria Nutt; Anti-inflammatory effect; Anti-fibrotic effect
7.  Notch1 downregulation combined with interleukin-24 inhibits invasion and migration of hepatocellular carcinoma cells 
AIM: To confirm the anti-invasion and anti-migration effects of down-regulation of Notch1 combined with interleukin (IL)-24 in hepatocellular carcinoma (HCC) cells.
METHODS: γ-secretase inhibitors (GSIs) were used to down-regulate Notch1. HepG2 and SMMC7721 cells were seeded in 96-well plates and treated with GSI-I or/and IL-24 for 48 h. Cell viability was measured by MTT assay. The cellular and nuclear morphology was observed under a fluorescence microscope. To further verify the apoptotic phenotype, cell cultures were also analyzed by flow cytometry with Annexin V-FITC/propidium iodide staining. The expression of Notch1, SNAIL1, SNAIL2, E-cadherin, IL-24, XIAP and VEGF was detected by Western blot. The invasion and migration capacities of HCC cells were detected by wound healing assays. Notch1 and Snail were down-regulated by RNA interference, and the target proteins were analyzed by Western blot. To investigate the mechanism of apoptosis, we analyzed HepG2 cells treated with siNotch1 or siCON plus IL-24 or not for 48 h by caspase-3/7 activity luminescent assay.
RESULTS: GSI-I at a dose of 2.5 μmol/L for 24 h caused a reduction in cell viability of about 38% in HepG2 cells. The addition of 50 ng/mL IL-24 in combination with 1 or 2.5 μmol/L GSI-I reduced cell viability of about 30% and 15%, respectively. Treatment with IL-24 alone did not induce any cytotoxic effect. In SMMC7721 cells with the addition of IL-24 to GSI-I (2.5 μmol/L), the reduction of cell viability was only about 25%. Following GSI-I/IL-24 combined treatment for 6 h, the apoptotic rate of HepG2 cells was 47.2%, while no significant effect was observed in cells treated with the compounds employed separately. Decreased expression of Notch1 and its associated proteins SNAIL1 and SNAIL2 was detected in HepG2 cells. Increased E-cadherin protein expression was noted in the presence of IL-24 and GSI-I. Furthermore, the increased GSI-I and IL-24 in HepG2 cell was associated with downregulation of MMP-2, XIAP and VEGF. In the absence of treatment, HepG2 cells could migrate into the scratched space in 24 h. With IL-24 or GSI-I treatment, the wound was still open after 24 h. And the distance of the wound closure strongly correlated with the concentrations of IL-24 and GSI-I. Treatment of Notch-1 silenced HepG2 cells with 50 ng/mL IL-24 alone for 48 h induced cytotoxic effects very similar to those observed in non-silenced cells treated with GSI-I/IL-24 combination. Caspase-3/7 activity was increased in the presence of siNotch1 plus IL-24 treatment.
CONCLUSION: Down-regulation of Notch1 by GSI-I or siRNA combined with IL-24 can sensitize apoptosis and decrease the invasion and migration capabilities of HepG2 cells.
PMCID: PMC4562956  PMID: 26361419
Notch signaling pathway; Interleukin-24; γ-secretase inhibitor; Invasion; Migration; Hepatocellular carcinoma
8.  Malat1 as an evolutionarily conserved lncRNA, plays a positive role in regulating proliferation and maintaining undifferentiated status of early-stage hematopoietic cells 
BMC Genomics  2015;16(1):676.
The metastasis-associated lung adenocarcinoma transcription 1 (Malat1) is a highly conserved long non-coding RNA (lncRNA) gene. Previous studies showed that Malat1 is abundantly expressed in many tissues and involves in promoting tumor growth and metastasis by modulating gene expression and target protein activities. However, little is known about the biological function and regulation mechanism of Malat1 in normal cell proliferation.
In this study we conformed that Malat1 is highly conserved across vast evolutionary distances amongst 20 species of mammals in terms of sequence, and found that mouse Malat1 expresses in tissues of liver, kidney, lung, heart, testis, spleen and brain, but not in skeletal muscle. After treating erythroid myeloid lymphoid (EML) cells with All-trans Retinoic Acid (ATRA), we investigated the expression and regulation of Malat1 during hematopoietic differentiation, the results showed that ATRA significantly down regulates Malat1 expression during the differentiation of EML cells. Mouse LRH (Lin-Rhodaminelow Hoechstlow) cells that represent the early-stage progenitor cells show a high level of Malat1 expression, while LRB (Lin − HoechstLow RhodamineBright) cells that represent the late-stage progenitor cells had no detectable expression of Malat1.
Knockdown experiment showed that depletion of Malat1 inhibits the EML cell proliferation. Along with the down regulation of Malat1, the tumor suppressor gene p53 was up regulated during the differentiation. Interestingly, we found two p53 binding motifs with help of bioinformatic tools, and the following chromatin immunoprecipitation (ChIP) test conformed that p53 acts as a transcription repressor that binds to Malat1’s promoter. Furthermore, we testified that p53 over expression in EML cells causes down regulation of Malat1.
In summary, this study indicates Malat1 plays a critical role in maintaining the proliferation potential of early-stage hematopoietic cells. In addition to its biological function, the study also uncovers the regulation pattern of Malat1 expression mediated by p53 in hematopoietic differentiation. Our research shed a light on exploring the Malat1 biological role including therapeutic significance to inhibit the proliferation potential of malignant cells.
PMCID: PMC4559210  PMID: 26335021
Malat1; lncRNA; ATRA; Hematopoiesis; EML; p53
9.  The interplay between histone deacetylases and c-Myc in the transcriptional suppression of HPP1 in colon cancer 
Cancer Biology & Therapy  2014;15(9):1198-1207.
HPP1 (hyperplastic polyposis protein 1), a tumor suppressor gene, is downregulated by promoter hypermethylation in a number of tumor types including colon cancer. c-Myc is also known to play a role in the suppression of HPP1 expression via binding to a promoter region cognate E-box site. The contribution of histone deacetylation as an additional epigenetic mechanism and its potential interplay with c-Myc in the transcriptional regulation of HPP1 are unknown. We have shown that the treatment of the HPP1-non-expressing colon cancer cell lines, HCT116 and DLD-1 with HDAC inhibitors results in re-expression of HPP1. RNAi-mediated knockdown of c-Myc as well as of HDAC2 and HDAC3 in HCT116 and of HDAC1 and HDAC3 in DLD-1 also resulted in significant re-expression of HPP1. Co-immunoprecipitation (IP), chromatin IP (ChIP), and sequential ChIP experiments demonstrated binding of c-Myc to the HPP1 promoter with recruitment of and direct interaction with HDAC3. In summary, we have demonstrated that c-Myc contributes to the epigenetic regulation of HPP1 via the dominant recruitment of HDAC3. Our findings may lead to a greater biologic understanding for the application of targeted use of HDAC inhibitors for anti-cancer therapy.
PMCID: PMC4128862  PMID: 24919179
colon cancer; epigenetics; histone acetylase; histone deacetylase inhibitors; Myc; HPP1
10.  Reemergence and Autochthonous Transmission of Dengue Virus, Eastern China, 2014 
Emerging Infectious Diseases  2015;21(9):1670-1673.
In 2014, 20 dengue cases were reported in the cities of Wenzhou (5 cases) and Wuhan (15 cases), China, where dengue has rarely been reported. Dengue virus 1 was detected in 4 patients. Although most of these cases were likely imported, epidemiologic analysis provided evidence for autochthonous transmission.
PMCID: PMC4550164  PMID: 26292098
Dengue virus; viruses; phylogeny; evolution; autochthonous transmission; vector-borne infections; Aedes aegypti; mosquitoes; Fujian; Thailand; Surinam; India; Bangladesh; Sri Lanka; China
11.  Disease Related Knowledge Summarization Based on Deep Graph Search 
BioMed Research International  2015;2015:428195.
The volume of published biomedical literature on disease related knowledge is expanding rapidly. Traditional information retrieval (IR) techniques, when applied to large databases such as PubMed, often return large, unmanageable lists of citations that do not fulfill the searcher's information needs. In this paper, we present an approach to automatically construct disease related knowledge summarization from biomedical literature. In this approach, firstly Kullback-Leibler Divergence combined with mutual information metric is used to extract disease salient information. Then deep search based on depth first search (DFS) is applied to find hidden (indirect) relations between biomedical entities. Finally random walk algorithm is exploited to filter out the weak relations. The experimental results show that our approach achieves a precision of 60% and a recall of 61% on salient information extraction for Carcinoma of bladder and outperforms the method of Combo.
PMCID: PMC4561941  PMID: 26413521
13.  GIT2 deficiency attenuates concanavalin A-induced hepatitis in mice 
FEBS Open Bio  2015;5:688-704.
•GIT2 depletion attenuates Con A-induced immunological hepatic injuries.•GIT2 depletion suppressed the activation and function of mouse CD4+ T cells.•GIT2 depletion suppressed liver infiltration by lymphoid cells after Con A treatment.•There were lower levels of proinflammatory cytokines in Git2−/− mice after Con A injection.
G protein-coupled receptor kinase interactor 2 (GIT2) is a signaling scaffold protein involved in regulation of cytoskeletal dynamics and the internalization of G protein-coupled receptors (GPCRs). The short-splice form of GIT2 is expressed in peripheral T cells and thymocytes. However, the functions of GIT2 in T cells have not yet been determined. We show that treatment with Con A in a model of polyclonal T-lymphocyte activation resulted in marked inhibitions in the intrahepatic infiltration of inflammatory cells, cytokine response and acute liver failure in Git2−/− mice. CD4+ T cells from Git2−/− mice showed significant impairment in proliferation, cytokine production and signal transduction upon TCR-stimulated activation. Our results suggested that GIT2 plays an important role in T-cell function in vivo and in vitro.
PMCID: PMC4556731  PMID: 26380813
GIT2, G protein-coupled receptor kinase interactor 2; FACS, fluorescence-activated cell sorting; GFP, green fluorescent protein; TCR, T cell receptor; Con A, concanavalin A; PMA, 4b-phorbol 12-myristate 13-acetate; GIT2; Hepatitis; Knock-out mice; Innate immunity; T cell activation
14.  Wilson disease with hepatic presentation in an eight-month-old boy 
Wilson disease is an autosomal recessive disorder of copper metabolism that can cause fatal neurological and hepatic disease if not diagnosed and treated. The youngest child with normal liver function reported so far is an 8-mo-old Japanese boy with low ceruloplasmin levels, and the youngest child with elevated aminotransferase ever reported so far is a 9-mo-old Korean boy with confirmed by genetic testing. Here we report an 8-mo-old Chinese boy presented with elevated liver enzymes, and low serum ceruloplasmin level. Genetic analysis of ATP7B gene detected two heterozygous disease causing mutations (c.2621C>T/p.A874V and c.3809A>G/p.N1270S), and parental origins were determined. Persistent elevation of serum aminotransferase in this infant was normalized after zinc therapy. To our best knowledge, this is the youngest patient with elevated liver enzymes ever reported worldwide. We hope that this will raise awareness among pediatricians, leading to earlier diagnosis, timely treatment, and better clinical outcome.
PMCID: PMC4528042  PMID: 26269689
Wilson disease; Infant; Hepatic presentation; ATP7B; Copper; Zinc
15.  Annular ligament reconstruction by suture anchor for treatment of radial head dislocation in children 
We investigated the efficacy of annular ligament reconstruction by suture anchor in the treatment of radial head dislocation (RHD) in children.
A total of 20 RHD children nderwent annular ligament reconstruction surgery using suture anchor. Preoperative and postoperative elbow functions were evaluated according to Broberg and Morrey 100-point scale. Recovery of radial nerve function was assessed using the Chinese Medical Association of Hand Surgery Branch of Upper Limb Functional Assessment Standard. All statistical analyses were performed using SPSS version 17.0 software.
All 20 RHD children who underwent the procedure were followed up for a median duration of 24 months. At the last follow-up, the average Broberg-Morrey score was 94.3, with 12 children (60.0 %) showing excellent outcomes (score range, 95 to 100), 7 children (35.0 %) showing good outcomes (score range, 80 to 94), 1 child (5.0 %) displayed a fair outcome (score range, 60 to 79), and 0 (0 %) poor outcome. A significant difference in the excellent-good rate was observed when the elbow function before surgery was compared to after surgery (χ2 = 5.559, P = 0.018). The radial nerve function of the 13 RHD children with radial nerve injury also recovered to normal. Among these 13 RHD children, nine exhibited excellent outcomes, 3 showed good outcomes, 1 displayed a fair outcome, and no patient showed a poor outcome. A significant difference in the excellent-good rate of radial nerve function was also observed when before surgery was compared to after surgery in these RHD children (χ2 = 4.887, P = 0.027).
Our results strongly indicated that suture anchor is highly effective for reconstruction of the annular ligament and to promote full functional recovery in RHD children, demonstrating that the procedure is an excellent treatment choice in RHD children.
PMCID: PMC4525736  PMID: 26242600
Radial head dislocation; Suture anchor; Annular ligament reconstruction; Broberg and Morrey 100-point scale; Radial nerve function; Functional recovery
16.  Huangqin-Tang Ameliorates TNBS-Induced Colitis by Regulating Effector and Regulatory CD4+ T Cells 
BioMed Research International  2015;2015:102021.
Huangqin-Tang decoction (HQT) is a classic traditional Chinese herbal formulation that is widely used to ameliorate the symptoms of gastrointestinal disorders, including inflammatory bowel disease (IBD). This study was designed to investigate the therapeutic potential and immunological regulatory activity of HQT in experimental colitis in rats. Using an animal model of colitis by intrarectally administering 2,4,6-trinitrobenzenesulfonic acid (TNBS), we found that administration of HQT significantly inhibited the severity of TNBS-induced colitis in a dose-dependent manner. In addition, treatment with HQT produced better results than that with mesalazine, as shown by improvedweight loss bleeding and diarrhoea scores, colon length, and intestinal inflammation. As for potential immunological regulation of HQT action, the percentages of Th1 and Th17 cells were reduced, but those Th2 and Treg cells were enhanced in LPMCs after HQT treatment. Additionally, HQT lowered the levels of Th1/Th17-associated cytokines but increased production of Th2/Treg-associated cytokines in the colon and MLNs. Furthermore, we observed a remarkable suppression of the Th1/Th17-associated transcription factors T-bet and ROR-γt. However, expression levels of the Th2/Treg-associated transcription factors GATA-3 and Foxp3 were enhanced during treatment with HQT. Our results suggest that HQT has the therapeutic potential to ameliorate TNBS-induced colitis symptoms. This protective effect is possibly mediated by its effects on CD4+ T cells subsets.
PMCID: PMC4539427  PMID: 26347453
17.  The Calcineurin-NFAT Axis Controls Allograft Immunity in Myeloid-Derived Suppressor Cells through Reprogramming T Cell Differentiation 
Molecular and Cellular Biology  2014;35(3):598-609.
While cyclosporine (CsA) inhibits calcineurin and is highly effective in prolonging rejection for transplantation patients, the immunological mechanisms remain unknown. Herein, the role of calcineurin signaling was investigated in a mouse allogeneic skin transplantation model. The calcineurin inhibitor CsA significantly ameliorated allograft rejection. In CsA-treated allograft recipient mice, CD11b+ Gr1+ myeloid-derived suppressor cells (MDSCs) were functional suppressive immune modulators that resulted in fewer gamma interferon (IFN-γ)-producing CD8+ T cells and CD4+ T cells (TH1 T helper cells) and more interleukin 4 (IL-4)-producing CD4+ T cells (TH2) and prolonged allogeneic skin graft survival. Importantly, the expression of NFATc1 is significantly diminished in the CsA-induced MDSCs. Blocking NFAT (nuclear factor of activated T cells) with VIVIT phenocopied the CsA effects in MDSCs and increased the suppressive activities and recruitment of CD11b+ Gr1+ MDSCs in allograft recipient mice. Mechanistically, CsA treatment enhanced the expression of indoleamine 2,3-dioxygenase (IDO) and the suppressive activities of MDSCs in allograft recipients. Inhibition of IDO nearly completely recovered the increased MDSC suppressive activities and the effects on T cell differentiation. The results of this study indicate that MDSCs are an essential component in controlling allograft survival following CsA or VIVIT treatment, validating the calcineurin-NFAT-IDO signaling axis as a potential therapeutic target in transplantation.
PMCID: PMC4285420  PMID: 25452304
18.  Human Adenovirus Type 7 Infection Associated with Severe and Fatal Acute Lower Respiratory Illness and Nosocomial Transmission 
Journal of Clinical Microbiology  2014;53(2):746-749.
A 23-year-old male died of severe pneumonia and respiratory failure in a tertiary hospital in Beijing, and 4 out of 55 close contacts developed fever. Molecular analysis confirmed human adenovirus type 7 (HAdV7) as the causative agent. We highlight the importance of early diagnosis and treatment and proper transmission control of HAdV7.
PMCID: PMC4298532  PMID: 25520444
19.  miR-198 Represses the Proliferation of HaCaT Cells by Targeting Cyclin D2 
Background: MiR-198 has been considered as an inhibitor of cell proliferation, invasion, migration and a promoter of apoptosis in most cancer cells, while its effect on non-cancer cells is poorly understood. Methods: The effect of miR-198 transfection on HaCaT cell proliferation was firstly detected using Cell Count Kit-8 and the cell cycle progression was analyzed by flow cytometry. Using bioinformatics analyses and luciferase assay, a new target of miR-198 was searched and identified. Then, the effect of the new target gene of miR-198 on cell proliferation and cell cycle was also detected. Results: Here we showed that miR-198 directly bound to the 3′-UTR of CCND2 mRNA, which was a key regulator in cell cycle progression. Overexpressed miR-198 repressed CCND2 expression at mRNA and protein levels and subsequently led to cell proliferation inhibition and cell cycle arrest in the G1 phase. Transfection ofSiCCND2 in HaCaT cells showed similar inhibitory effects on cell proliferation and cell cycle progression. Conclusion: In conclusion, we have identified that miR-198 inhibited HaCaT cell proliferation by directly targeting CCND2.
PMCID: PMC4581182  PMID: 26225959
miR-198; cyclin D2; HaCaT; cell proliferation
20.  Competition between RNA-binding proteins CELF1 and HuR modulates MYC translation and intestinal epithelium renewal 
Molecular Biology of the Cell  2015;26(10):1797-1810.
ELAV-like family member 1, or CELF1, competes with another RNA-binding protein, HuR, to modulate MYC translation and plays an important role in the regulation of intestinal epithelial renewal.
The mammalian intestinal epithelium is one of the most rapidly self-renewing tissues in the body, and its integrity is preserved through strict regulation. The RNA-binding protein (RBP) ELAV-like family member 1 (CELF1), also referred to as CUG-binding protein 1 (CUGBP1), regulates the stability and translation of target mRNAs and is implicated in many aspects of cellular physiology. We show that CELF1 competes with the RBP HuR to modulate MYC translation and regulates intestinal epithelial homeostasis. Growth inhibition of the small intestinal mucosa by fasting in mice was associated with increased CELF1/Myc mRNA association and decreased MYC expression. At the molecular level, CELF1 was found to bind the 3′-untranslated region (UTR) of Myc mRNA and repressed MYC translation without affecting total Myc mRNA levels. HuR interacted with the same Myc 3′-UTR element, and increasing the levels of HuR decreased CELF1 binding to Myc mRNA. In contrast, increasing the concentrations of CELF1 inhibited formation of the [HuR/Myc mRNA] complex. Depletion of cellular polyamines also increased CELF1 and enhanced CELF1 association with Myc mRNA, thus suppressing MYC translation. Moreover, ectopic CELF1 overexpression caused G1-phase growth arrest, whereas CELF1 silencing promoted cell proliferation. These results indicate that CELF1 represses MYC translation by decreasing Myc mRNA association with HuR and provide new insight into the molecular functions of RBPs in the regulation of intestinal mucosal growth.
PMCID: PMC4436827  PMID: 25808495
21.  The Rapid Screening of Triazophos Residues in Agricultural Products by Chemiluminescent Enzyme Immunoassay 
PLoS ONE  2015;10(7):e0133839.
A highly sensitive chemiluminescent enzyme immunoassay (CLEIA) method was developed in this study for efficient screening of triazophos residues in a large number of samples. Based on the maximum residue limits (MRLs) set by China and CAC for triazophos in different agro-products, the representative apple, orange, cabbage, zucchini, and rice samples were selected as spiked samples, and the triazophos at the concentrations of the MRL values were spiked to blank samples. Subsequently, the five samples with the spiked triazophos standard were measured by CLEIA 100 times, and the detection results indicated that the correction factors of the apple, orange, cabbage, zucchini, and rice were determined as 0.79, 0.66, 0.85, 0.76, and 0.91, respectively. In this experiment, 1500 real samples were detected by both the CLEIA and the GC-MS methods. With the GC-MS method, 1462 samples were identified as negative samples and 38 samples as positive samples. Based on the correction factors, the false positive rate of the CLEIA method was 0.13%, and false negative rate was 0. The results showed that the established CLEIA method could be used to screen a large number of real samples.
PMCID: PMC4517747  PMID: 26218576
22.  Massive interstitial copy-neutral loss-of-heterozygosity as evidence for cancer being a disease of the DNA-damage response 
BMC Medical Genomics  2015;8:42.
The presence of loss-of-heterozygosity (LOH) mutations in cancer cell genomes is commonly encountered. Moreover, the occurrences of LOHs in tumor suppressor genes play important roles in oncogenesis. However, because the causative mechanisms underlying LOH mutations in cancer cells yet remain to be elucidated, enquiry into the nature of these mechanisms based on a comprehensive examination of the characteristics of LOHs in multiple types of cancers has become a necessity.
We performed next-generation sequencing on inter-Alu sequences of five different types of solid tumors and acute myeloid leukemias, employing the AluScan platform which entailed amplification of such sequences using multiple PCR primers based on the consensus sequences of Alu elements; as well as the whole genome sequences of a lung-to-liver metastatic cancer and a primary liver cancer. Paired-end sequencing reads were aligned to the reference human genome to identify major and minor alleles so that the partition of LOH products between homozygous-major vs. homozygous-minor alleles could be determined at single-base resolution. Strict filtering conditions were employed to avoid false positives. Measurements of LOH occurrences in copy number variation (CNV)-neutral regions were obtained through removal of CNV-associated LOHs.
We found: (a) average occurrence of copy-neutral LOHs amounting to 6.9 % of heterologous loci in the various cancers; (b) the mainly interstitial nature of the LOHs; and (c) preference for formation of homozygous-major over homozygous-minor, and transitional over transversional, LOHs.
The characteristics of the cancer LOHs, observed in both AluScan and whole genome sequencings, point to the formation of LOHs through repair of double-strand breaks by interhomolog recombination, or gene conversion, as the consequence of a defective DNA-damage response, leading to a unified mechanism for generating the mutations required for oncogenesis as well as the progression of cancer cells.
Electronic supplementary material
The online version of this article (doi:10.1186/s12920-015-0104-2) contains supplementary material, which is available to authorized users.
PMCID: PMC4515014  PMID: 26208496
Copy number variation; Double strand break repair; Gain-of-heterozygosity; Gene conversion; Inter-homologous recombination; Loss-of-heterozygosity
23.  U-shaped relationship between early blood glucose and mortality in critically ill children 
BMC Pediatrics  2015;15:88.
The aims of this study are to evaluate the relationship between early blood glucose concentrations and mortality and to define a ‘safe range’ of blood glucose concentrations during the first 24 h after pediatric intensive care unit (PICU) admission with the lowest risk of mortality. We further determine whether associations exist between PICU mortality and early hyperglycemia and hypoglycemia occurring within 24 h of PICU admission, even after adjusting for illness severity assessed by the pediatric risk of mortality III (PRISM III) score.
This retrospective cohort study included patients admitted to PICU between July 2008 and June 2011 in a tertiary teaching hospital. Both the initial admission glucose values and the mean glucose values over the first 24 h after PICU admission were analyzed.
Of the 1349 children with at least one blood glucose value taken during the first 24 h after admission, 129 died during PICU stay. When analyzing both the initial admission and mean glucose values during the first 24 h after admission, the mortality rate was compared among children with glucose concentrations ≤65, 65-90, 90–110, 110–140, 140–200, and >200 mg/dL (≤3.6, 3.6–5.0, 5.0–6.1, 6.1–7.8, 7.8–11.1, and >11.1 mmol/L). Children with glucose concentrations ≤65 mg/dL (3.6 mmol/L) and >200 mg/dL (11.1 mmol/L) had significantly higher mortality rates, indicating a U-shaped relationship between glucose concentrations and mortality. Blood glucose concentrations of 110–140 mg/dL (6.1–7.8 mmol/L), followed by 90–110 mg/dL (5.0–6.1 mmol/L), were associated with the lowest risk of mortality, suggesting that a ‘safe range’ for blood glucose concentrations during the first 24 h after admission in critically ill children exists between 90 and 140 mg/dL (5.0 and 7.8 mmol/L). The odds ratios of early hyperglycemia (>140 mg/dL [7.8 mmol/L]) and hypoglycemia (≤65 mg/dL [3.6 mmol/L]) being associated with increased risk of mortality were 4.13 and 15.13, respectively, compared to those with mean glucose concentrations of 110–140 mg/dL (6.1–7.8 mmol/L) (p <0.001). The association remained significant after adjusting for PRISM III scores (p <0.001).
There was a U-shaped relationship between early blood glucose concentrations and PICU mortality in critically ill children. Both early hyperglycemia and hypoglycemia were associated with mortality, even after adjusting for illness severity.
PMCID: PMC4513674  PMID: 26204931
Critically ill children; Glucose; Hyperglycemia; Hypoglycemia; Intensive care; Mortality; Pediatric; Pediatric risk of mortality III
24.  Altered microRNAs expression profiling in cumulus cells from patients with polycystic ovary syndrome 
Polycystic ovary syndrome (PCOS) is a common endocrine disorder in women of reproductive age, and oocyte developmental competence is altered in patients with PCOS. In recent years microRNAs (miRNAs) have emerged as important regulators of gene expression, the aim of the study was to study miRNAs expression patterns of cumulus cells from PCOS patients.
The study included 20 patients undergoing in vitro fertilization (IVF) and intra-cytoplasmic sperm injection (ICSI): 10 diagnosed with PCOS and 10 matching controls. We used deep sequencing technology to identify the miRNAs differentially expressed in the cumulus cells of PCOS.
There were 17 differentially expressed miRNAs in PCOS cumulus cells, including 10 miRNAs increase and 7 miRNAs decrease. These miRNAs were predicted to target a large set of genes with different functions, including Wnt- and MAPK- signaling pathways, oocyte meiosis, progesterone-mediated oocyte maturation and cell cycle. Unsupervised hierarchical clustering analysis demonstrated that there was a specific miRNAs expression pattern in PCOS cumulus cells.
We found that the miRNAs expression profile was different in cumulus cells isolated from PCOS patients compared with control. This study provided new evidence for understanding the pathogenesis of PCOS.
PMCID: PMC4508762  PMID: 26198660
Polycystic ovary syndrome; MicroRNAs; Cumulus cells; Expression profile
25.  Downregulation of KIF1B mRNA in hepatocellular carcinoma tissues correlates with poor prognosis 
AIM: To compare kinesin family member 1B (KIF1B) expression with clinicopathologic parameters and prognosis in hepatocellular carcinoma (HCC) patients.
METHODS: KIF1B protein and mRNA expression was assessed in HCC and paracarcinomatous (PC) tissues from 68 patients with HCC using Western blot and quantitative real-time reverse transcription-PCR, respectively. Student’s t-tests were used to analyze relationships between clinicopathologic parameters and KIF1B expression, the Kaplan-Meier method was used to analyze survival outcomes, and the log-rank test was used to compare survival differences between groups.
RESULTS: Mean protein and mRNA levels of KIF1B were similar between HCC and PC tissues. However, HCC tissues with vein invasions had significantly lower KIF1B protein levels compared to those without vein invasions (2.30 ± 0.82 relative units vs 2.77 ± 0.84 relative units, P < 0.05). KIF1B protein levels in HCC tissues from patients with recurrence during the follow-up period were significantly lower than those without recurrence (2.31 ± 0.92 relative units vs 2.80 ± 0.80 relative units, P < 0.05). However, KIF1B protein and mRNA expression in HCC patients was not associated with other clinicopathologic parameters. Ratios of KIF1B mRNA expression in HCC tissues to those in PC tissues were correlated with overall survival (13.5 mo vs 20.0 mo, P < 0.05) and disease-free survival (11.5 mo vs 19.5 mo, P < 0.05).
CONCLUSION: Downregulation of KIF1B in HCC tissues is associated with poor prognosis; additional clinical studies are needed to confirm whether KIF1B can serve as a prognostic marker.
PMCID: PMC4507112  PMID: 26217094
Clinicopathologic correlation; Kinesin family member 1B; Liver cancer; Survival; Tumor progression

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