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1.  ABCB5 maintains melanoma-initiating cells through a pro-inflammatory cytokine signaling circuit 
Cancer research  2014;74(15):4196-4207.
The drug efflux transporter ABCB5 identifies cancer stem-like cells (CSC) in diverse human malignancies, where its expression is associated with clinical disease progression and tumor recurrence. ABCB5 confers therapeutic resistance but other functions in tumorigenesis independent of drug efflux have not been described that might help explain why it is so broadly overexpressed in human cancer. Here we show that in melanoma-initiating cells ABCB5 controls IL-1β secretion which serves to maintain slow-cycling, chemoresistant cells through an IL-1β/IL8/CXCR1 cytokine signaling circuit. This CSC maintenance circuit involved reciprocal paracrine interactions with ABCB5-negative cancer cell populations. ABCB5 blockade induced cellular differentiation, reversed resistance to multiple chemotherapeutic agents, and impaired tumor growth in vivo. Together, our results defined a novel function for ABCB5 in CSC maintenance and tumor growth.
PMCID: PMC4119553  PMID: 24934811
Melanoma; ABCB5; Interleukin-1β; Interleukin-8; CXCR1
2.  ABCB5 is a limbal stem cell gene required for corneal development and repair 
Nature  2014;511(7509):353-357.
Corneal epithelial homeostasis and regeneration are sustained by limbal stem cells (LSCs)1–3, and LSC deficiency is a major cause of blindness worldwide4. Transplantation is often the only therapeutic option available to patients with LSC deficiency. However, while transplant success depends foremost on LSC frequency within grafts5, a gene allowing for prospective LSC enrichment has not been identified so far5. Here we show that ATP-binding cassette, sub-family B, member 5 (ABCB5)6,7 marks LSCs and is required for LSC maintenance, corneal development and repair. Furthermore, we demonstrate that prospectively isolated human or murine ABCB5-positive LSCs possess the exclusive capacity to fully restore the cornea upon grafting to LSC-deficient mice in xenogeneic or syngeneic transplantation models. ABCB5 is preferentially expressed on label-retaining LSCs2 in mice and p63α-positive LSCs8 in humans. Consistent with these findings, ABCB5-positive LSC frequency is reduced in LSC-deficient patients. Abcb5 loss of function in Abcb5 knockout mice causes depletion of quiescent LSCs due to enhanced proliferation and apoptosis, and results in defective corneal differentiation and wound healing. Our results from gene knockout studies, LSC tracing and transplantation models, as well as phenotypic and functional analyses of human biopsy specimens, provide converging lines of evidence that ABCB5 identifies mammalian LSCs. Identification and prospective isolation of molecularly defined LSCs with essential functions in corneal development and repair has important implications for the treatment of corneal disease, particularly corneal blindness due to LSC deficiency.
PMCID: PMC4246512  PMID: 25030174
3.  Photon Devil’s staircase: photon long-range repulsive interaction in lattices of coupled resonators with Rydberg atoms 
Scientific Reports  2015;5:11510.
The realization of strong coherent interactions between individual photons is a long-standing goal in science and engineering. In this report, based on recent experimental setups, we derive a strong photon long-range repulsive interaction, by controlling the van der Waals repulsive force between Cesium Rydberg atoms located inside different cavities in extended Jaynes-Cummings-Hubbard lattices. We also find novel quantum phases induced by this photon long-range repulsive interaction. For example, without photon hopping, a photon Devil’s staircase, induced by the breaking of long-range translation symmetry, can emerge. If photon hopping occurs, we predict a photon-floating solid phase, due to the motion of particle- and hole-like defects. More importantly, for a large chemical potential in the resonant case, the photon hopping can be frozen even if the hopping term exists. We call this new phase the photon-frozen solid phase. In experiments, these predicted phases could be detected by measuring the number of polaritons via resonance fluorescence.
PMCID: PMC4479987  PMID: 26108705
4.  Non-thermal plasma treatment altered gene expression profiling in non-small-cell lung cancer A549 cells 
BMC Genomics  2015;16(1):435.
Recent technological advances in atmospheric plasmas have made the creation of non-thermal atmospheric pressure plasma (NTP) possible for utilization in the medical field. Although accumulated evidence suggests that NTP induces cell death in various cancer cell types thus offering a promising alternative treatment strategy, the mechanism underlying its therapeutic effect is not fully understood.
We analyzed relevant signaling cascades associated with the tumor protein p53, in particular the cell cycle arrest, DNA damage as well as the underlying apoptosis pathways. Based on our results, the major effect from plasma exposure was found to be the activation of MAPK and p53 signaling pathways, resulting in changes in gene expression of MEKK, GADD, FOS and JUN. Finally, a significant modulation in expression of genes related to cellular proliferation and differentiation was observed.
Overall, the presented data of the tumor transcriptome helped identify the key players in modulated gene expression following exposure to plasma at the molecular level, and also helped interpret the downstream processes. The present work laid the foundation for further studies to clarify the roles of multiple pathways in plasma-induced biological processes. Further investigation of these genes in other cell lines may reveal comprehensive mechanisms of plasma induced effects.
Electronic supplementary material
The online version of this article (doi:10.1186/s12864-015-1644-8) contains supplementary material, which is available to authorized users.
PMCID: PMC4483225  PMID: 26116417
Non-thermal plasma; Gene profiling; NSCLC A549 cell line; Multiple signal pathways
5.  Nestin depletion induces melanoma matrix metalloproteinases and invasion 
Matrix metalloproteinases (MMPs) are key biological mediators of processes as diverse as wound healing, embryogenesis, and cancer progression. Although MMPs may be induced through multiple signaling pathways, the precise mechanisms for their regulation in cancer are incompletely understood. Because cytoskeletal changes are known to accompany MMP expression, we sought to examine the potential role of the poorly understood cytoskeletal protein, nestin, in modulating melanoma MMPs. Nestin knockdown (KD) upregulated expression of specific MMPs and MMP-dependent invasion both through extracellular matrix barriers in vitro and in peritumoral connective tissue of xenografts in vivo. Development of 3-dimensionsal melanospheres that in vitro partially recapitulate non-invasive tumorigenic melanoma growth was inhibited by nestin KD, although ECM invasion by aberrant melanospheres that did form was enhanced. Mechanistically, nestin KD-dependent melanoma invasion was associated with intracellular redistribution of phosphorylated focal adhesion kinase (pFAK) and increased melanoma cell responsiveness to transforming growth factor-beta (TGF-β), both implicated in pathways of melanoma invasion. The results suggest that the heretofore poorly understood intermediate filament, nestin, may serve as a novel mediator of MMPs critical to melanoma virulence.
PMCID: PMC4419570  PMID: 25365206
FAK; invasion; matrix metalloproteinase; melanoma; nestin; TGF-β
6.  Exosomes Derived from Human Umbilical Cord Mesenchymal Stem Cells Relieve Acute Myocardial Ischemic Injury 
Stem Cells International  2015;2015:761643.
This study is aimed at investigating whether human umbilical cord mesenchymal stem cell- (hucMSC-) derived exosomes (hucMSC-exosomes) have a protective effect on acute myocardial infarction (AMI). Exosomes were characterized under transmission electron microscopy and the particles of exosomes were further examined through nanoparticle tracking analysis. Exosomes (400 μg protein) were intravenously administrated immediately following ligation of the left anterior descending (LAD) coronary artery in rats. Cardiac function was evaluated by echocardiography and apoptotic cells were counted using TUNEL staining. The cardiac fibrosis was assessed using Masson's trichrome staining. The Ki67 positive cells in ischemic myocardium were determined using immunohistochemistry. The effect of hucMSC-exosomes on blood vessel formation was evaluated through tube formation and migration of human umbilical vein endothelial cells (EA.hy926 cells). The results indicated that ligation of the LAD coronary artery reduced cardiac function and induced cardiomyocyte apoptosis. Administration of hucMSC-exosomes significantly improved cardiac systolic function and reduced cardiac fibrosis. Moreover, hucMSC-exosomes protected myocardial cells from apoptosis and promoted the tube formation and migration of EA.hy926 cells. It is concluded that hucMSC-exosomes improved cardiac systolic function by protecting myocardial cells from apoptosis and promoting angiogenesis. These effects of hucMSC-exosomes might be associated with regulating the expression of Bcl-2 family.
PMCID: PMC4461782  PMID: 26106430
7.  Effects and Mechanism of Atmospheric-Pressure Dielectric Barrier Discharge Cold Plasma on Lactate Dehydrogenase (LDH) Enzyme 
Scientific Reports  2015;5:10031.
Proteins are carriers of biological functions and the effects of atmospheric-pressure non-thermal plasmas on proteins are important to applications such as sterilization and plasma-induced apoptosis of cancer cells. Herein, we report our detailed investigation of the effects of helium-oxygen non-thermal dielectric barrier discharge (DBD) plasmas on the inactivation of lactate dehydrogenase (LDH) enzyme solutions. Circular dichroism (CD) and dynamic light scattering (DLS) indicate that the loss of activity stems from plasma-induced modification of the secondary molecular structure as well as polymerization of the peptide chains. Raising the treatment intensity leads to a reduced alpha-helix content, increase in the percentage of the beta-sheet regions and random sequence, as well as gradually decreasing LDH activity. However, the structure of the LDH plasma-treated for 300 seconds exhibits a recovery trend after storage for 24 h and its activity also increases slightly. By comparing direct and indirect plasma treatments, plasma-induced LDH inactivation can be attributed to reactive species (RS) in the plasma, especially ones with a long lifetime including hydrogen peroxide, ozone, and nitrate ion which play the major role in the alteration of the macromolecular structure and molecular diameter in lieu of heat, UV radiation, and charged particles.
PMCID: PMC4438714  PMID: 25992482
8.  Human adipose-derived stem cells partially rescue the stroke syndromes by promoting spatial learning and memory in mouse middle cerebral artery occlusion model 
Growing evidence has brought stem cell therapy to the forefront as new promising approaches towards stroke treatment. Of all candidate seeding cells, adipose-derived stem cells (ADSCs) are considered as one of the most appropriate for stroke treatment. However, previous experimental data could not reach to an agreement on the efficacy of ADSC transplantation for treating stroke in vivo as well as its mechanism which hinders their further clinical translational application.
To explore their in vivo mechanism of hADSC administration on neurological injury, hADSC were labeled with Enhanced Green Fluorescence Protein expressing FG12 lentivirus and injected into MCAO mouse infarct area by in situ way. Neurological function was evaluated by Rogers Scaling System and their spatial learning and memory was determined by Morris Test. 2,3,5-triphenyltetrazolium chloride was carried out to compare the infarct area among groups. Histoimmunostaining was used to track the injected hADSCs for their in vivo migration, transdifferentiation and integration with the endogenous neuronal circuitry. To better address the underlying rescuing mechanism, qRT-PCR was performed on neural markers of MBP, MAP2, GFAP, microglia marker of Iba1.
It was found that hADSCs could promote both spatial learning and memory of MCAO mice. Co-localization of GFP and MAP2 were found in the whole cortex with significantly (P<0.01) higher percentage at the contralateral cortex compared with the ipsilateral cortex. Low percentage of GFP and GFAP co-localized cells were found at whole cortex. Meanwhile, Iba1+ microglia and GFAP+ astrocyte cells were significantly (P<0.05) suppressed by hADSC injection.
hADSCs could transdifferentiate into neuron like cells (MAP2+) in vivo and probably used as seeding cells for replacement based stem cell therapy of stroke. Also, significant immunomodulation was found. Meanwhile hADSCs could significantly protect the endogenous neuron survival. This study demonstrated that hADSC intervention with MCAO mice could apparently ameliorate stroke symptoms by direct cell replacement, enhanced immnunosuppression and increasing the viability of endogenous neurons.
Electronic supplementary material
The online version of this article (doi:10.1186/s13287-015-0078-1) contains supplementary material, which is available to authorized users.
PMCID: PMC4453264  PMID: 25956259
9.  T-helper 2 Cytokines, Transforming Growth Factor β1, and Eosinophil Products Induce Fibrogenesis and Alter Muscle Motility in Patients with Eosinophilic Esophagitis 
Gastroenterology  2014;146(5):1266-1277.e9.
Patients with eosinophilic esophagitis (EoE) often become dysphagic from the combination of organ fibrosis and motor abnormalities. We investigated mechanisms of dysphagia, assessing the response of human esophageal fibroblasts (HEF), muscle cells (HEMC), and esophageal muscle strips to eosinophil-derived products.
Biopsies were collected via endoscopy from the upper, middle and lower thirds of the esophagus of 18 patients with EoE and 21 individuals undergoing endoscopy for other reasons (controls). Primary cultures of esophageal fibroblasts and muscle cells were derived from 12 freshly resected human esophagectomy specimens. Eosinophil distribution was investigated by histologic analyses of full-thickness esophageal tissue. Active secretion of EoE-related mediators was assessed from medium underlying mucosal biopsy cultures. We quantified production of fibronectin and collagen I by HEF and HEMC in response to eosinophil products. We also measured expression of ICAM1 and VCAM1 by, and adhesion of human eosinophils to, HEF and HEMC. Eosinophil products were tested in an esophageal muscle contraction assay.
Activated eosinophils were present in all esophageal layers. Significantly higher concentrations of eosinophil-related mediators were spontaneously secreted in mucosal biopsies from patients with EoE than controls. Exposure of HEF and HEMC to increasing concentrations of eosinophil products or co-culture with eosinophils caused HEF and HEMC to increase secretion of fibronectin and collagen I; this was inhibited by blocking transforming growth factor (TGF)β1 and p38 mitogen-activated protein kinase (MAKP) signaling. Eosinophil binding to HEF and HEMC increased following incubation of mesenchymal cells with eosinophil-derived products, and decreased following blockade of TGFβ1 and p38MAPK blockade. Eosinophil products reduced electrical field-induced contraction of esophageal muscle strips, but not acetylcholine-induced contraction.
In an analysis of tissues samples from patients with EoE, we linked the presence and activation state of eosinophils in EoE with altered fibrogenesis and motility of esophageal fibroblasts and muscle cells. This process might contribute to the development of dysphagia.
PMCID: PMC3992171  PMID: 24486052
Primary human cells; transmural disease; swallowing; immune regulation
10.  Lysosome and Cytoskeleton Pathways Are Robustly Enriched in the Blood of Septic Patients: A Meta-Analysis of Transcriptomic Data 
Mediators of Inflammation  2015;2015:984825.
Background. Sepsis is a leading cause of mortality in intensive care units worldwide. A better understanding of the blood systems response to sepsis should expedite the identification of biomarkers for early diagnosis and therapeutic interventions. Methods. We analyzed microarray studies whose data is available from the GEO repository and which were performed on the whole blood of septic patients and normal controls. Results. We identified 6 cohorts consisting of 450 individuals (sepsis = 323, control = 127) providing genome-wide messenger RNA (mRNA) expression data. Through meta-analysis we found the “Lysosome” and “Cytoskeleton” pathways were upregulated in human sepsis patients relative to controls, in addition to previously known signaling pathways (including MAPK, TLR). The key regulatory genes in the “Lysosome” pathway include lysosomal acid hydrolases (e.g., protease cathepsin A, D) as well as the major (LAMP1, 2) and minor (SORT1, LAPTM4B) membrane proteins. In contrast, pathways related to “Ribosome”, “Spliceosome” and “Cell adhesion molecules” were found to be downregulated, along with known pathways for immune dysfunction. Overall, our study revealed distinct mRNA activation profiles and protein-protein interaction networks in blood of human sepsis. Conclusions. Our findings suggest that aberrant mRNA expression in the lysosome and cytoskeleton pathways may play a pivotal role in the molecular pathobiology of human sepsis.
PMCID: PMC4430672  PMID: 26063982
11.  Transplantation of Human Neural Progenitor Cells Expressing IGF-1 Enhances Retinal Ganglion Cell Survival 
PLoS ONE  2015;10(4):e0125695.
We have previously characterized human neuronal progenitor cells (hNP) that can adopt a retinal ganglion cell (RGC)-like morphology within the RGC and nerve fiber layers of the retina. In an effort to determine whether hNPs could be used a candidate cells for targeted delivery of neurotrophic factors (NTFs), we evaluated whether hNPs transfected with an vector that expresses IGF-1 in the form of a fusion protein with tdTomato (TD), would increase RGC survival in vitro and confer neuroprotective effects in a mouse model of glaucoma. RGCs co-cultured with hNPIGF-TD cells displayed enhanced survival, and increased neurite extension and branching as compared to hNPTD or untransfected hNP cells. Application of various IGF-1 signaling blockers or IGF-1 receptor antagonists abrogated these effects. In vivo, using a model of glaucoma we showed that IOP elevation led to reductions in retinal RGC count. In this model, evaluation of retinal flatmounts and optic nerve cross sections indicated that only hNPIGF-TD cells effectively reduced RGC death and showed a trend to improve optic nerve axonal loss. RT-PCR analysis of retina lysates over time showed that the neurotrophic effects of IGF-1 were also attributed to down-regulation of inflammatory and to some extent, angiogenic pathways. This study shows that neuronal progenitor cells that hone into the RGC and nerve fiber layers may be used as vehicles for local production and delivery of a desired NTF. Transplantation of hNPIGF-TD cells improves RGC survival in vitro and protects against RGC loss in a rodent model of glaucoma. Our findings have provided experimental evidence and form the basis for applying cell-based strategies for local delivery of NTFs into the retina. Application of cell-based delivery may be extended to other disease conditions beyond glaucoma.
PMCID: PMC4414591  PMID: 25923430
13.  Web Resources for Mass Spectrometry-based Proteomics 
With the development of high-resolution and high-throughput mass spectrometry (MS) technology, a large quantum of proteomic data is continually being generated. Collecting and sharing these data are a challenge that requires immense and sustained human effort. In this report, we provide a classification of important web resources for MS-based proteomics and present rating of these web resources, based on whether raw data are stored, whether data submission is supported, and whether data analysis pipelines are provided. These web resources are important for biologists involved in proteomics research.
PMCID: PMC4411487  PMID: 25721607
Mass spectrometry; Proteomics; Web resources
14.  The Anti-Cancer Potency and Mechanism of a Novel Tumor-Activated Fused Toxin, DLM 
Toxins  2015;7(2):423-438.
Melittin, which acts as a membrane-disrupting lytic peptide, is not only cytotoxic to tumors, but also vital to normal cells. Melittin had low toxicity when coupled with target peptides. Despite significant research development with the fused toxin, a new fused toxin is needed which has a cleavable linker such that the fused toxin can release melittin after protease cleavage on the tumor cell surface. We describe a novel fused toxin, composed of disintegrin, uPA (urokinase-type plasminogen activator)-cleavable linker, and melittin. Disintegrin is a single strand peptide (73 aa) isolated from Gloydius Ussuriensis venom. The RGD (Arg-Gly-Asp) site of disintegrin dominates its interaction with integrins on the surface of the tumor cells. uPA is over-expressed and plays an important role in tumor cell invasiveness and metastatic progression. The DLM (disintegrin-linker-melittin) linker is uPA-cleavable, enabling DLM to release melittin. We compared binding activity of our synthesized disintegrin with native disintegrin and report that DLM had less binding activity than the native form. uPA-cleavage was evaluated in vitro and the uPA-cleavable linker released melittin. Treating tumors expressing uPA with DLM enhanced tumor cell killing as well as reduced toxicity to erythrocytes and other non-cancerous normal cells. The mechanism behind DLM tumor cell killing was tested using a DNA ladder assay, fluorescent microscopy, flow cytometry, and transmission electron microscopy. Data revealed tumor cell necrosis as the mechanism of cell death, and the fused DLM toxin with an uPA-cleavable linker enhanced tumor selectivity and killing ability.
PMCID: PMC4344633  PMID: 25658509
tumor-activated; fused toxin; disintegrin; melittin; anti-cancer
15.  Obesity and Risk of Thyroid Cancer: Evidence from a Meta-Analysis of 21 Observational Studies 
Several studies have evaluated the association between obesity and thyroid cancer risk. However, the results remain uncertain. In this study, we conducted a meta-analysis to assess the association between obesity and thyroid cancer risk.
Published literature from PubMed, EMBASE, Springer Link, Ovid, Chinese Wanfang Data Knowledge Service Platform, Chinese National Knowledge Infrastructure (CNKI), and Chinese Biology Medicine (CBM) were retrieved before 10 August 2014. We included all studies that reported adjusted risk ratios (RRs), hazard ratios (HRs) or odds ratios (ORs), and 95% confidence intervals (CIs) of thyroid cancer risk.
Thirty-two studies (n=12 620 676) were included in this meta-analysis. Obesity was associated with a significantly increased risk of thyroid cancer (adjusted RR=1.33; 95% CI, 1.24–1.42; I2=25%). In the subgroup analysis by study type, increased risk of thyroid cancer was found in cohort studies and case-control studies. In subgroup analysis by sex, both obese men and women were at significantly greater risk of thyroid cancer than non-obese subjects. When stratified by ethnicity, significantly elevated risk was observed in Caucasians and in Asians. In the age subgroup analysis, both young and old populations showed increased thyroid cancer risk. Subgroup analysis on smoking status showed that increased thyroid cancer risks were found in smokers and in non-smokers. In the histology subgroup analyses, increased risks of papillary thyroid cancer, follicular thyroid cancer, and anaplastic thyroid cancer were observed. However, obesity was associated with decreased risk of medullary thyroid cancer.
Our results indicate that obesity is associated with an increased thyroid cancer risk, except medullary thyroid cancer.
PMCID: PMC4315628  PMID: 25612155
Meta-Analysis; Obesity; Thyroid Neoplasms
16.  Zoledronic Acid May Reduce Intraoperative Bleeding in Spinal Tumors: A Prospective Cohort Study 
BioMed Research International  2015;2015:936307.
Between June 2010 and June 2011, 176 patients were divided into 2 groups: a group with spinal metastasis of solid tumors (n = 157) and a group with multiple myeloma (n = 19). Both groups were further divided into 2 subgroups: a group receiving zoledronic acid before surgery and a control group. The zoledronic acid subgroup of the solid tumors group was group A (n = 81), the control subgroup of the solid tumors group was group B (n = 76), the zoledronic acid subgroup of the multiple myeloma group was group C (n = 10), and the control subgroup of the multiple myeloma group was group D (n = 9). The average intraoperative blood loss during spinal surgery was as follows: 1311 ± 691 mL in group A and 1752 ± 740 mL in group B (P = 0.000) and 1994 ± 810 mL in group C and 3134 ± 795 mL in group D (P = 0.000). Patients receiving zoledronic acid before surgery had significantly less intraoperative bleeding than those who did not receive it. Preoperative use of zoledronic acid can effectively reduce intraoperative bleeding during surgery for the treatment of spinal tumors.
PMCID: PMC4317594  PMID: 25685817
17.  MicroRNAs associated with osteoarthritis differently expressed in bone matrix gelatin (BMG) rat model 
Osteoarthritis (OA) is characterized by degeneration of articular cartilage, limited intraarticular inflammation with synovitis, and changes in peri-articular and subchondral bone. In recent years, more and more evidence demonstrated that microRNAs (miRNAs) play important roles in the molecular mechanisms in OA by suppressing gene expression at the post-transcriptional level. In current study, histological staining of toluidine blue and cartilage-specific gene express revealed that the bone matrix gelatin (BMG) rat model could demonstrate the different development of cartilage. In current study, we tested whether some miRNAs associated with OA differently expressed in BMG rat model. We verified that miR-140 and miR-455 were associated with cartilage development, and further revealed that miR-140-5p and miR-455-3p might play more important function than miR-140-3p and miR-455-5p in the BMG rat model. Moreover, we found that miR-9 and miR-98 were involved in the endochondral ossification, suggesting they may be also the key regulators in the process of endochondral ossification. In fact, many miRNAs worked as a miRNA-mediated regulatory network in the process of cartilage development and OA. Further functional discovery will clarify the roles of individual miRNAs and their targets, and serve as a strong foundation for translating these findings to the clinic therapy for OA.
PMCID: PMC4358542  PMID: 25785087
Osteoarthritis; microRNA; BMG rat model
18.  Utility of plasma fibrinogen in the differential diagnosis of thyrotoxicosis 
Background: A study had reported that a low TSH level is associated with elevated plasma fibrinogen (FIB) levels. Our purpose was to investigate the role of FIB in the differential diagnosis of thyrotoxicosis. Methods: The data of 104 patients with primary thyrotoxicosis at the First Hospital of China Medical University from July 2010 to March 2011 were analyzed and divided into three groups: 45 cases of subacute thyroiditis, 50 cases of Graves’ disease, and 9 cases of toxic multinodular goiter. The patients with subacute thyroiditis were followed up before and after the treatment. FIB levels of the three groups were compared. Results: There was no significant difference in serum TSH, FT3 and FT4 between the patients with three different causes of thyrotoxicosis (P > 0.05). The proportion of hyperfibrinogenemia in patients with subacute thyroiditis was 98%. The FIB levels of patients with subacute thyroiditis were significantly higher than those with Graves’ disease and toxic multinodular goiter (P < 0.05). Levels of ESR show a similar tendency. The FIB levels returned to normal with the remission of subacute thyroiditis. Conclusions: Elevated plasma fibrinogen is a common manifestation of the active phase of subacute thyroiditis. A FIB test can be used for the differential diagnosis of thyrotoxicosis. We can anticipate the outcome of subacute thyroiditis through the dynamic changes of FIB.
PMCID: PMC4358571  PMID: 25785116
Fibrinogen; thyrotoxicosis; subacute thyroiditis; diagnosis
19.  Culture medium of bone marrow-derived human mesenchymal stem cells effects lymphatic endothelial cells and tumor lymph vessel formation 
Oncology Letters  2015;9(3):1221-1226.
Human bone marrow mesenchymal stem cells (hBM-MSCs) favor tumor growth and metastasis in vivo and in vitro. Neovascularization is involved in several pathological conditions, including tumor growth and metastasis. Previous studies have demonstrated that human bone marrow MSC-derived conditioned medium (hBM-MSC-CM) can promote tumor growth by inducing the expression of vascular epidermal growth factor (VEGF) in tumor cells. However, the effect of BM-MSCs on tumor lymph vessel formation has yet to be elucidated. In the present study, the effect of BM-MSCs on processes involved in lymph vessel formation, including tube formation, migration and proliferation, was investigated in human-derived lymphatic endothelial cells (HDLECs). It was identified that hBM-MSC-CM promoted the tube formation and migration of HDLECs. In addition, tumor cells were revealed to participate in lymph vessel formation. In the present study, the SGC-7901, HGC-27 and GFP-MCF-7 cell lines were treated with hBM-MSC-CM. The results demonstrated that the expression of the lymph-associated markers, prospero homeobox protein 1 and VEGF receptor-3, were increased in the SGC-7901 and HGC-27 cell lines, but not in the GFP-MCF-7 cells. The tube formation assay demonstrated that the HGC-27 cells treated with hBM-MSC-CM for 20 days underwent tube formation. These findings indicate that hBM-MSC-CM can promote tube formation in HDLECs and HGC-27 cells, which may be associated with lymph vessel formation during tumor growth and metastasis.
PMCID: PMC4315037  PMID: 25663886
mesenchymal stem cell; lymph vessel; tumor growth
20.  Effect of small nuclear ribonucleoprotein-associated polypeptide N on the proliferation of medulloblastoma cells 
Molecular Medicine Reports  2015;11(5):3337-3343.
Spliceosome mutations have been reported in various types of cancer and a number of antitumor drugs have been observed to tightly bind to spliceosome components. Small nuclear ribonucleoprotein-associated polypeptide N (SNRPN) is a small ribonuclear protein and is a key spliceosome constituent. However, the role of SNRPN in human medulloblastoma remains unknown. In the present study, the effect of SNRPN on cell growth was investigated in vitro using the Daoy human medulloblastoma cell line. Lentivirus (Lv)-mediated short hairpin (sh) RNA was used to silence SNRPN expression, which was verified by reverse transcription-quantitative polymerase chain reaction and western blotting. Cell proliferation was examined by MTT and colony formation assays. Knockdown of SNRPN markedly reduced the proliferation and colony formation ability of Daoy medulloblastoma cells. In addition, flow cytometric analysis revealed that the cell cycle distribution was altered when the Daoy cells were infected with Lv-shSNRPN. To the best of our knowledge, this is the first study to investigate the effect of SNRPN on cell proliferation in medulloblastoma. The results indicate that SNRPN may be a potential novel target for the development of pharmacological therapeutics in human medulloblastoma.
PMCID: PMC4368083  PMID: 25571951
proliferation; small nuclear ribonucleoprotein-associated polypeptide N; medulloblastoma; short hairpin RNA
21.  Digital PCR quantification of miRNAs in sputum for diagnosis of lung cancer 
MicroRNAs (miRNAs) play important roles in the initiation and progression of lung cancer. Measuring miRNA expression levels in sputum could provide a potential approach for the diagnosis of lung cancer. The emerging digital PCR is a straightforward technique for precise, direct, and absolute quantification of nucleic acids. The objective of the study was to investigate whether digital PCR could be used to quantify miRNAs in sputum for lung cancer diagnosis.
We first determined and compared dynamic ranges of digital PCR and conventional quantitative reverse transcriptase PCR (qRT-PCR) for miRNA quantification using RNA isolated from sputum of five healthy individuals. We then used digital PCR to quantify copy number of two lung cancer-associated miRNAs (miR-31 and miR-210) in 35 lung cancer patients and 40 cancer-free controls.
Copy number of the miRNAs measured by digital PCR displayed a linear response to input cDNA amount in a twofold dilution series over seven orders of magnitude. miRNA quantification determined by digital PCR assay was in good agreement with that obtained from qRT-PCR analysis in sputum. Furthermore, combined quantification of miR-31 and miR-210 copy number by using digital PCR in sputum of the cases and controls provided 65.71 % sensitivity and 85.00 % specificity for lung cancer diagnosis.
As digital PCR becomes more established, it would be a robust tool for quantitative assessment of miRNA copy number in sputum for lung cancer diagnosis.
PMCID: PMC3898839  PMID: 24281335
Digital PCR; miRNAs; Sputum; Diagnosis; Lung cancer
22.  Prognostic significance and clinicopathological features of hypoxic inducible factor-2alpha expression in hepatocellular carcinoma 
Saudi Medical Journal  2015;36(2):170-175.
To assess the association between hypoxic inducible factor-2alpha (HIF-2α) and hepatocellular carcinoma (HCC) by meta-analysis.
This study was carried out at Anhui Province Hospital, Hefei, Anhui, China in February 2014. We searched various databases for studies published in English or Chinese up to February 28, 2014. The hazard ratio for overall survival and analyzed odds ratio were combined to evaluate the clinicopathological features of HIF-2α expression in HCC.
A total of 7 eligible studies comprising 1066 patients with HCC were identified after our full assessment according to inclusion criteria. All of the patients came from China. The results indicated that the association between HIF-2α expression and prognostic values in HCC was inconspicuous, while the expression of HIF-2α was significantly associated with capsule infiltration, vein invasion, and histological grade.
Expression of HIF-2α was associated with invasion and metastasis in HCC, but did not have a distinct significance in prognosis, according to the limited evidence. However, high quality, large sample size, and controlled trials are required.
PMCID: PMC4375693  PMID: 25719580
23.  Th17/Treg Cells Imbalance and GITRL Profile in Patients with Hashimoto’s Thyroiditis 
Hashimoto’s thyroiditis (HT) is an organ-specific immune disease characterized by the presence of lymphocytic infiltration and serum autoantibodies. Previous studies have confirmed the critical role of Th17 cells in the pathopoiesis of HT patients. Additionally, regulatory T cells (Treg) display a dysregulatory function in autoimmune disease. The purpose of this study is to investigate the alteration of Th17 and Treg cells in HT patients and explore contributing factors. We found there was an increased ratio of Th17/Treg in HT patients and a positive correlation with autoantibodies (anti-TgAb). In addition, there was an increased level of GITRL, which has been demonstrated to be correlated with the increassement of Th17 cells in the serum and thyroid glands of HT patients; the upregulated serum level of GITRL has a positive correlation with the percentage of Th17 cells in HT patients. In summary, an increase in GITRL may impair the balance of Th17/Treg, and contribute to the pathopoiesis of Hashimoto’s thyroiditis.
PMCID: PMC4284671  PMID: 25429429
Hashimoto’s thyroiditis; Th17 cells; Treg cells; GITRL
24.  Non-small cell lung cancer with EML4-ALK translocation in Chinese male never-smokers is characterized with early-onset 
BMC Cancer  2014;14:834.
The translocations of the anaplastic lymphoma kinase (ALK) gene with the echinoderm microtubule-associated protein-like 4 (EML4) gene on chromosome 2p have been identified in non-small-cell lung cancers (NSCLCs) as oncogenic driver mutations. It has been suggested that EML4-ALK fusion is associated with the resistance in NSCLCs to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs), such as gefitinib and erlotinib. In contrast, ALK tyrosine kinase inhibitor (ALK TKI) crizotinib has shown superior effects in combating NSCLCs with EML4-ALK. Thus, characterization of EML4-ALK fusion genes and clinical features of resulting carcinomas would be a great benefit to disease diagnosis and designing customized treatment plans. Studies have suggested that EML4-ALK translocation occurs more frequently in never-smokers with NSCLC, especially in female patients. However, it is not clear whether this is the case in male patients, too. In this study, we have determined the frequency of EML4-ALK translocation in male never-smokers with NSCLC in a cohort of Chinese patients. The clinical features associated with EML4-ALK translocation were also investigated.
A cohort of 95 Chinese male never-smokers with NSCLC was enrolled in this study. EML4-ALK fusion genes were detected using one-step real time RT-PCR and DNA sequencing. We further determined the expression levels of ALK mRNA by RT-PCR and ALK protein by immunohistochemistry in these specimens. The clinical features of EML4-ALK–positive carcinomas were also determined.
We have identified EML4-ALK fusion genes in 8 out of 95 carcinoma cases, accounting for 8.42% in Chinese male never-smokers with NSCLC. It is significantly higher than that in all Chinese male patients (3.44%) regardless smoking habit. It is also significantly higher than that in all Chinese smokers (8/356 or 2.25%) or in smokers worldwide (2.9%) by comparing to published data. Interestingly, EML4-ALK fusion genes are more frequently found in younger patients and associated with less-differentiated carcinomas.
The frequency of EML4-ALK translocation is strongly associated with smoking habits in Chinese male patients with higher frequency in male never-smokers. EML4-ALK translocation is associated with early-onset and less-differentiated carcinomas.
PMCID: PMC4240865  PMID: 25407901
Non-small-cell lung cancers (NSCLCs); Anaplastic lymphoma kinase (ALK); Echinoderm microtubule-associated protein-like 4 (EML4); Tyrosine kinase inhibitors (TKIs); Never-smokers; Adenocarcinoma
25.  Esophageal Adenocarcinoma and Its Rare Association with Barrett’s Esophagus in Henan, China 
PLoS ONE  2014;9(10):e110348.
Incidence of esophageal adenocarcinoma (EAC) has increased sharply in Western Europe and United States over the past three decades. Nearly all cases of EAC in the west are thought to be associated with Barrett’s esophagus (BE) at the time of diagnosis. Regions in the Henan province of China have one of world’s highest incidences of esophageal cancer, yet recent temporal trends in the relative rates of EAC with respect to esophageal squamous-cell carcinoma (ESCC), as well as its association with Barrett’s esophagus (BE), have not been reported. In this report, we present large-scale longitudinal clinical and histological data on 5401 esophageal cancers (EC) patients diagnosed during the recent 10-year period (2002–2011) at Henan Cancer Hospital, China. All 217 esophageal adenocarcinoma (EAC) patients from these 5401 EC patients were examined to better understand the relationship between Barrett’s esophagus (BE) and EAC. We found that EAC was relatively rare and accounted for approximately 5% of all esophageal cancers each year during 2002–2011. There is no evidence of significant temporal trends in the rate of EAC relative to ESCC. Only 10 out of 217 (4.6%) EAC cases were detected to have any evidence of Barrett’s esophagus. This result raises the possibility of a different etiological basis for EAC in China motivating more detailed epidemiological, clinical and molecular characterization of EAC in China in order to better understand the neoplastic development of EAC.
PMCID: PMC4198241  PMID: 25333822

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