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2.  In vivo direct reprogramming of reactive glial cells into functional neurons after brain injury and in an Alzheimer’s disease model 
Cell stem cell  2013;14(2):188-202.
Summary
Loss of neurons after brain injury and in neurodegenerative disease is often accompanied by reactive gliosis and scarring, which are difficult to reverse with existing treatment approaches. Here, we show that reactive glial cells in the cortex of stab-injured or Alzheimer’s disease (AD) model mice can be directly reprogrammed into functional neurons in vivo using retroviral expression of a single neural transcription factor, NeuroD1. Following expression of NeuroD1, astrocytes were reprogrammed into glutamatergic neurons, while NG2 cells were reprogrammed into glutamatergic and GABAergic neurons. Cortical slice recordings revealed both spontaneous and evoked synaptic responses in NeuroD1-converted neurons, suggesting that they integrated into local neural circuits. NeuroD1 expression was also able to reprogram cultured human cortical astrocytes into functional neurons. Our studies therefore suggest that direct reprogramming of reactive glial cells into functional neurons in vivo could provide an alternative approach for repair of injured or diseased brain.
doi:10.1016/j.stem.2013.12.001
PMCID: PMC3967760  PMID: 24360883
NeuroD1; reactive astrocytes; NG2 cells; reprogram; in vivo; Alzheimer’s disease; brain injury; cortex; neurons
3.  Chronic alcohol exposure exacerbates inflammation and triggers pancreatic acinar-to-ductal metaplasia through PI3K/Akt/IKK 
Pancreatic acinar-to-ductal metaplasia (ADM) has been identified as an initiating event that can progress to pancreatic intraepithelial neoplasia (PanIN) or pancreatic ductal adenocarcinoma (PDAC). Acini transdifferentiation can be induced by persistent inflammation. Notably, compelling evidence has emerged that chronic alcohol exposure may trigger an inflammatory response of macrophages/monocytes stimulated by endotoxins. In the present study, we aimed to evaluate the role of inflammation induced by chronic alcohol and lipopolysaccharide (LPS) exposure in the progression of pancreatic ADM, as well as to elucidate the possible mechanisms involved. For this purpose, cultured macrophages were exposed to varying doses of alcohol for 1 week prior to stimulation with LPS. Tumor necrosis factor-α (TNF-α) and regulated upon activation, normal T cell expression and secreted (RANTES) expression were upregulated in the intoxicated macrophages with activated nuclear factor-κB (NF-κB). Following treatment with the supernatant of intoxicated macrophages, ADM of primary acinar cells was induced. Furthermore, the expression of TNF-α and RANTES, as well as the phosphatidylinositol-3-kinase (PI3K)/protein kinase B(Akt)/inhibitory κB kinase (IKK) signaling pathway have been proven to be involved in the ADM of acinar cells. Moreover, Sprague-Dawley (SD) rats were employed to further explore the induction of pancreatic ADM by chronic alcohol and LPS exposure in vivo. At the end of the treatment period, a number of physiological parameters, such as body weight, liver weight and pancreatic weight were reduced in the exposed rats. Plasma alcohol concentrations and oxidative stress levels in the serum, as well as TNF-α and RANTES expression in monocytes were also induced following chronic alcohol and LPS exposure. In addition, pancreatic ADM was induced through the PI3K/Akt/IKK signaling pathway by the augmented TNF-α and RANTES expression levels in the exposed rats. Overall, we characterized the link between inflammation induced by chronic alcohol and LPS exposure and pancreatic ADM. However, the mechanisms behind the induction of pancreatic ADM warrant further investigation.
doi:10.3892/ijmm.2014.2055
PMCID: PMC4314411  PMID: 25573338
chronic alcohol, lipopolysaccharide; acinar-to-ductal metaplasia; PI3K/Akt/IKK
4.  Tonic inhibition in dentate gyrus impairs long-term potentiation and memory in an Alzhiemer’s disease model 
Nature communications  2014;5:4159.
SUMMARY
Amyloid plaques and tau tangles are common pathological hallmarks for Alzheimer’s disease (AD), however reducing Aβ production failed to relieve the symptoms of AD patients. Here we report a high GABA (γ-aminobutyric acid) content in reactive astrocytes in the dentate gyrus (DG) of a mouse model for AD (5xFAD) that results in increased tonic inhibition and memory deficit. We also confirm in human AD patient brains that dentate astrocytes have a high GABA content, suggesting that high astrocytic GABA level may be a novel biomarker and a potential diagnostic tool for AD. The excessive GABA in 5xFAD astrocytes is released through an astrocyte-specific GABA transporter GAT3/4, and significantly enhanced tonic GABA inhibition in dentate granule cells. Importantly, reducing tonic inhibition in 5xFAD mice rescues the impairment of long-term potentiation (LTP) and memory deficit. Thus, reducing tonic GABA inhibition in the DG may lead to a novel therapy for Alzheimer’s disease.
doi:10.1038/ncomms5159
PMCID: PMC4159602  PMID: 24923909
Alzheimer’s disease; astrocyte; GABA transporter; GAT3; GAT4; GABAA receptor; α5 subunit; tonic inhibition; dentate gyrus; long-term potentiation; memory deficit; drug target; biomarker
5.  A large inflammatory myofibroblastic tumor involving both stomach and spleen: A case report and review of the literature 
Oncology Letters  2014;9(2):811-815.
Inflammatory myofibroblastic tumor (IMT) is a rare, benign neoplasm that most commonly occurs in pediatric patients; it has been described as a pseudosarcomatous proliferation of spindled myofibroblasts mixed with lymphoplasmacytic cells. IMT has been reported in a number of locations throughout the body; however, cases occurring in the gastrointestinal tract are rare and to date, no case involving both the stomach and spleen has been reported. The current study presents a case of an extremely large IMT invading both the stomach and spleen in a 50-year-old female, presenting with a three-month history of left-sided abdominal distension without abdominal pain, fever or vomiting. As the tumor had invaded the stomach and spleen, it was completely excised and concomitantly, the entire stomach and spleen were removed. Histological examination of the biopsy revealed fascicles of spindle cells in a mixed inflammatory background, with inflammatory cells that were immunopositive for vimentin, smooth muscle actin, and negative for anaplastic lymphoma kinase and CD30, confirming the diagnosis of IMT. Four months following local excision of the mass, accompanied by a total gastrectomy and splenectomy, no abdominal distension, abdominal pain, fever or vomiting were observed and no IMT recurrence was identified.
doi:10.3892/ol.2014.2761
PMCID: PMC4301536  PMID: 25624905
inflammatory myofibroblastic tumor; stomach; spleen; gastrointestinal stromal tumor
6.  Galanin neurons in the medial preoptic area govern parental behavior 
Nature  2014;509(7500):325-330.
Mice display robust, stereotyped behaviors toward pups: virgin males typically attack pups, while virgin females and sexually experienced males and females display parental care. We show here that virgin males genetically impaired in vomeronasal sensing do not attack pups and are parental. Further, we uncover a subset of galanin-expressing neurons in the medial preoptic area (MPOA) that are specifically activated during male and female parenting, and a different subpopulation activated during mating. Genetic ablation of MPOA galanin neurons results in dramatic impairment of parental responses in males and females and affects male mating. Optogenetic activation of these neurons in virgin males suppresses inter-male and pup-directed aggression and induces pup grooming. Thus, MPOA galanin neurons emerge as an essential regulatory node of male and female parenting behavior and other social responses. These results provide an entry point to a circuit-level dissection of parental behavior and its modulation by social experience.
doi:10.1038/nature13307
PMCID: PMC4105201  PMID: 24828191
7.  Neural control of maternal and paternal behaviors 
Science (New York, N.Y.)  2014;345(6198):765-770.
Parental care, including feeding and protection of young, is essential for the survival as well as mental and physical well-being of the offspring. A large variety of parental behaviors has been described across species and sexes, raising fascinating questions about how animals identify the young and how brain circuits drive and modulate parental displays in males and females. Recent studies have begun to uncover a striking antagonistic interplay between brain systems underlying parental care and infant-directed aggression in both males and females, as well as a large range of intrinsic and environmentally driven neural modulation and plasticity. Improved understanding of the neural control of parental interactions in animals should provide novel insights into the complex issue of human parental care in both health and disease.
doi:10.1126/science.1253291
PMCID: PMC4230532  PMID: 25124430
8.  MUC1 gene polymorphism rs4072037 and susceptibility to gastric cancer: a meta-analysis 
SpringerPlus  2014;3:599.
The association between MUC1 polymorphism rs4072037 and the risk of gastric cancer has been described in several studies. However, these studies yielded inconsistent results, especially in different pathological type of gastric cancer. Therefore, we performed this meta-analysis to evaluate the relationship between MUC1 gene polymorphism and gastric cancer susceptibility. A comprehensive database search was performed to identify eligible studies. Odds ratios with 95% confidence intervals were calculated to assess the strength of the association between MUC1 rs4072037 and risk of gastric cancer. Subgroup analyses, publication bias, and sensitivity analyses were also conducted. PubMed, EMBASE, Web of Science and CNKI databases were systematically searched to identify relevant studies. A total of 9 studies (12 datasets) were included in the meta-analysis including 10,410 cases and 11,437 controls. Overall, the G allele at rs4072037 of MUC1 gene was associated with a significant decreased gastric cancer risk (OR=0.70, 95% CI: 0.64–0.76). The association was significant in both anatomic location and pathological subtype subgroup analyses. However, the association was detected in Asian rather than Caucasian. Our findings demonstrate that the presence of the G allele at rs4072037 of the MUC1 gene may contribute to protection against gastric cancer in Asian. Further large studies of multiethnic groups are needed to validate these findings.
Electronic supplementary material
The online version of this article (doi:10.1186/2193-1801-3-599) contains supplementary material, which is available to authorized users.
doi:10.1186/2193-1801-3-599
PMCID: PMC4198476  PMID: 25332893
MUC1; Polymorphism; Genetic; Stomach neoplasms; Meta-analysis
9.  Trefoil factor 3 promotes metastatic seeding and predicts poor survival outcome of patients with mammary carcinoma 
Introduction
Recurrence or early metastasis remains the predominant cause of mortality in patients with estrogen receptor positive (ER+) mammary carcinoma (MC). However, the molecular mechanisms underlying the initial progression of ER+ MC to metastasis remains poorly understood. Trefoil factor 3 (TFF3) is an estrogen-responsive oncogene in MC. Herein, we provide evidence for a functional role of TFF3 in metastatic progression of ER+ MC.
Methods
The association of TFF3 expression with clinicopathological parameters and survival outcome in a cohort of MC patients was assessed by immunohistochemistry. The expression of TFF3 in MCF7 and T47D cells was modulated by forced expression or siRNA-mediated depletion of TFF3. mRNA and protein levels were determined using qPCR and western blot. The functional effect of modulation of TFF3 expression in MC cells was determined in vitro and in vivo. Mechanistic analyses were performed using reporter constructs, modulation of signal transducer and activator of transcription 3 (STAT3) expression, and pharmacological inhibitors against c-SRC and STAT3 activity.
Results
TFF3 protein expression was positively associated with larger tumour size, lymph node metastasis, higher stage, and poor survival outcome. Forced expression of TFF3 in ER+ MC cells stimulated colony scattering, cell adhesion to a Collagen I-coated matrix, colony formation on a Collagen I- or Matrigel-coated matrix, endothelial cell adhesion, and transmigration through an endothelial cell barrier. In vivo, forced expression of TFF3 in MCF7 cells stimulated the formation of metastatic nodules in animal lungs. TFF3 regulation of the mRNA levels of epithelial, mesenchymal, and metastatic-related genes in ER+ MC cells were consistent with the altered cell behaviour. Forced expression of TFF3 in ER+ MC cells stimulated phosphorylation of c-SRC that subsequently increased STAT3 activity, which lead to the downregulation of E-cadherin. siRNA-mediated depletion of TFF3 reduced the invasiveness of ER+ MC cells.
Conclusions
TFF3 expression predicts metastasis and poor survival outcome of patients with MC and functionally stimulates cellular invasion and metastasis of ER+ MC cells. Adjuvant functional inhibition of TFF3 may therefore be considered to ameliorate outcome of ER+ MC patients.
Electronic supplementary material
The online version of this article (doi:10.1186/s13058-014-0429-3) contains supplementary material, which is available to authorized users.
doi:10.1186/s13058-014-0429-3
PMCID: PMC4303111  PMID: 25266665
10.  Arginine deiminase augments the chemosensitivity of argininosuccinate synthetase-deficient pancreatic cancer cells to gemcitabine via inhibition of NF-κB signaling 
BMC Cancer  2014;14(1):686.
Background
Pancreatic cancer is a leading cause of cancer-related deaths in the world with a 5-year survival rate of less than 6%. Currently, there is no successful therapeutic strategy for advanced pancreatic cancer, and new effective strategies are urgently needed. Recently, an arginine deprivation agent, arginine deiminase, was found to inhibit the growth of some tumor cells (i.e., hepatocellular carcinoma, melanoma, and lung cancer) deficient in argininosuccinate synthetase (ASS), an enzyme used to synthesize arginine. The purpose of this study was to evaluate the therapeutic efficacy of arginine deiminase in combination with gemcitabine, the first line chemotherapeutic drug for patients with pancreatic cancer, and to identify the mechanisms associated with its anticancer effects.
Methods
In this study, we first analyzed the expression levels of ASS in pancreatic cancer cell lines and tumor tissues using immunohistochemistry and RT-PCR. We further tested the effects of the combination regimen of arginine deiminase with gemcitabine on pancreatic cancer cell lines in vitro and in vivo.
Results
Clinical investigation showed that pancreatic cancers with reduced ASS expression were associated with higher survivin expression and more lymph node metastasis and local invasion. Treatment of ASS-deficient PANC-1 cells with arginine deiminase decreased their proliferation in a dose- and time-dependent manner. Furthermore, arginine deiminase potentiated the antitumor effects of gemcitabine on PANC-1 cells via multiple mechanisms including induction of cell cycle arrest in the S phase, upregulation of the expression of caspase-3 and 9, and inhibition of activation of the NF-κB survival pathway by blocking NF-κB p65 signaling via suppressing the nuclear translocation and phosphorylation (serine 536) of NF-κB p65 in vitro. Moreover, arginine deiminase can enhance antitumor activity of gemcitabine-based chemotherapy in the mouse xenograft model.
Conclusions
Our results suggest that arginine deprivation by arginine deiminase, in combination with gemcitabine, may offer a novel effective treatment strategy for patients with pancreatic cancer and potentially improve the outcome of patients with pancreatic cancer.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2407-14-686) contains supplementary material, which is available to authorized users.
doi:10.1186/1471-2407-14-686
PMCID: PMC4189535  PMID: 25240403
11.  Prognostic Value of FGFR Gene Amplification in Patients with Different Types of Cancer: A Systematic Review and Meta-Analysis 
PLoS ONE  2014;9(8):e105524.
Background
Fibroblast growth factor receptor (FGFR) gene amplification has been reported in different types of cancer. We performed an up-to-date meta-analysis to further characterize the prognostic value of FGFR gene amplification in patients with cancer.
Methods
A search of several databases, including MEDLINE (PubMed), EMBASE, Web of Science, and China National Knowledge Infrastructure, was conducted to identify studies examining the association between FGFR gene amplification and cancer. A total of 24 studies met the inclusion criteria, and overall incidence rates, hazard risk (HR), overall survival, disease-free survival, and 95% confidence intervals (CIs) were calculated employing fixed- or random-effects models depending on the heterogeneity of the included studies.
Results
In the meta-analysis of 24 studies, the prevalence of FGFR gene amplification was FGFR1: 0.11 (95% CI: 0.08–0.13) and FGFR2: 0.04 (95% CI: 0.02–0.06). Overall survival was significantly worse among patients with FGFR gene amplification: FGFR1 [HR 1.57 (95% CI: 1.23–1.99); p = 0.0002] and FGFR2 [HR 2.27 (95% CI: 1.73–3.00); p<0.00001].
Conclusions
Current evidence supports the conclusion that the outcomes of patients with FGFR gene amplified cancers is worse than for those with non-FGFR gene amplified cancers.
doi:10.1371/journal.pone.0105524
PMCID: PMC4149366  PMID: 25171497
12.  1, 25(OH)2D3 Inhibits Hepatocellular Carcinoma Development Through Reducing Secretion of Inflammatory Cytokines from Immunocytes 
Current medicinal chemistry  2013;20(33):4131-4141.
Epidemiological and clinical studies have indicated that low vitamin D activity is not only associated with an increased cancer risk and a more aggressive tumor growth, but also connected with an aggravated liver damage caused by chronic inflammation. Meanwhile, increasing evidence has demonstrated that 1,25(OH)2D3 (the most biologically active metabolite of vitamin D) can inhibit inflammatory response in some chronic inflammatory associated cancer, which is considered to have the anti-tumor potency. However, the interaction between 1,25(OH)2D3 and inflammation during hepatocellular carcinoma (HCC) initiation and progression is not yet clear. Here, we report an anti-tumorigenesis effect of 1,25(OH)2D3 via decreasing inflammatory cytokine secretion in HCC and hypothesize the possible underlying mechanism. Firstly, we show that the enhanced tumor growth is associated with elevated inflammatory cytokine IL-6 and TNF-α in 1α(OH)ase gene-knockout mice. Secondly, 1,25(OH)2D3 can inhibit vitamin D receptor (VDR) shRNA interfered tumor cell growth through decreasing inflammatory cytokine secretion in vitro and in vivo. Finally, using p27kip1 gene knock-out mouse model, we demonstrate that the effect of 1,25(OH)2D3 in inhibiting immune cell related inflammatory cytokine secretion, exerts in a p27kip1 gene dependent way. Collectively, 1,25(OH)2D3 inhibits HCC development through up-regulating the expression of p27kip1 in immune cell and reducing inflammatory cytokine production.
PMCID: PMC4112515  PMID: 23992309
HCC; chronic inflammation; 1,25(OH)2D3; 1α(OH)ase; gene knockout; IL-6; TNF-α; STAT3 signaling; p27kip1; co-culture
13.  Necrolytic migratory erythema as the first manifestation of pancreatic neuroendocrine tumor 
Necrolytic migratory erythma (NME) is an obligatory paraneoplastic syndrome. Here we describe a woman admitted to the dermatology ward with NME which was later found to be associated with glucagonoma, a slow-growing, rare pancreatic neuroendocrine tumor. Even more rarely, the tumor was located in the pancreas head, while most of such lesions are located in the distal pancreas. The diagnosis of this rare tumor requires an elevated serum glucagon level and imaging confirming a pancreatic tumor. After surgical removal of the tumor, the patient’s cutaneous and systemic features resolved. It is therefore imperative that clinicians recognize NME early in order to make an accurate diagnosis and to provide treatment for this rare tumor.
doi:10.1186/1477-7819-12-220
PMCID: PMC4105234  PMID: 25029913
Necrolytic migratory erythema; Glucagonoma; Pancreatic neuroendocrine tumors
14.  B-cell lymphoma 6 protein stimulates oncogenicity of human breast cancer cells 
BMC Cancer  2014;14:418.
Background
B-cell lymphoma 6 (BCL6) protein, an evolutionarily conserved zinc finger transcription factor, showed to be highly expressed in various human cancers in addition to malignancies in the lymphoid system. This study investigated the role of BCL6 expression in breast cancer and its clinical significance in breast cancer patients.
Methods
Expression of BCL6 protein was assessed using in situ hybridization and immunohistochemistry in 127 breast cancer patients and 50 patients with breast benign disease as well as in breast cell lines. Expression of BCL6 was restored or knocked down in two breast cancer cell lines (MCF-7 and T47D) using BCL6 cDNA and siRNA, respectively. The phenotypic change of these breast cancer cell lines was assessed using cell viability MTT, Transwell invasion, colony formation, and flow cytometry assays and in a xenograft mice model. Luciferase reporter gene, immunoblot, and qRT-PCR were used to investigate the molecular events after manipulated BCL6 expression in breast cancer cells.
Results
BCL6 protein was highly expressed in breast cancer cell lines and tissue specimens and expression of BCL6 protein was associated with disease progression and poor survival of breast cancer patients. In vitro, the forced expression of BCL6 results in increased proliferation, anchorage-independent growth, migration, invasion and survival of breast cancer cell lines, whereas knockdown of BCL6 expression reduced these oncogenic properties of breast cancer cells. Moreover, forced expression of BCL6 increased tumor growth and invasiveness in a nude mouse xenograft model. At the gene level, BCL6 was a target gene of miR-339-5p. Expression of BCL6 induced expression of CXCR4 and cyclinD1 proteins.
Conclusions
The current study demonstrated the oncogenic property of BCL6 in breast cancer and further study could target BCL6 as a novel potential therapeutic strategy for breast cancer.
doi:10.1186/1471-2407-14-418
PMCID: PMC4065600  PMID: 24917186
Breast cancer; BCL6; microRNA
15.  Microsatellite markers for the invasive species Bidens alba (Asteraceae)1 
Applications in Plant Sciences  2014;2(5):apps.1400008.
• Premise of the study: Microsatellite markers were developed in the invasive species Bidens alba (Asteraceae) to assess its population structure and to facilitate tracking its expansion in China.
• Methods and Results: Using 454 pyrosequencing, 20 microsatellite primer sets were developed for B. alba. The markers were tested on one population of B. alba (30 individuals) and one population of the closely related B. pilosa (30 individuals) in China. For B. alba, all of the markers were polymorphic, and the number of alleles per locus ranged from three to 32. The expected heterozygosity values were from 0.3787 to 0.9284, and the Shannon–Wiener index was from 0.6796 to 2.8401.
• Conclusions: These markers will be useful for investigating the genetic structure, genetic diversity, and invasion dynamics of B. alba and will also be useful in studies of B. pilosa.
doi:10.3732/apps.1400008
PMCID: PMC4103112  PMID: 25202626
Asteraceae; Bidens alba; microsatellite marker; simple sequence repeat (SSR)
16.  Human colorectal cancer-specific CCAT1-L lncRNA regulates long-range chromatin interactions at the MYC locus 
Cell Research  2014;24(5):513-531.
The human 8q24 gene desert contains multiple enhancers that form tissue-specific long-range chromatin loops with the MYC oncogene, but how chromatin looping at the MYC locus is regulated remains poorly understood. Here we demonstrate that a long noncoding RNA (lncRNA), CCAT1-L, is transcribed specifically in human colorectal cancers from a locus 515 kb upstream of MYC. This lncRNA plays a role in MYC transcriptional regulation and promotes long-range chromatin looping. Importantly, the CCAT1-L locus is located within a strong super-enhancer and is spatially close to MYC. Knockdown of CCAT1-L reduced long-range interactions between the MYC promoter and its enhancers. In addition, CCAT1-L interacts with CTCF and modulates chromatin conformation at these loop regions. These results reveal an important role of a previously unannotated lncRNA in gene regulation at the MYC locus.
doi:10.1038/cr.2014.35
PMCID: PMC4011346  PMID: 24662484
CCAT1-L lncRNA; super-enhancer; chromatin looping; MYC; CTCF
17.  α-Mangostin Suppresses the Viability and Epithelial-Mesenchymal Transition of Pancreatic Cancer Cells by Downregulating the PI3K/Akt Pathway 
BioMed Research International  2014;2014:546353.
α-Mangostin, a natural product isolated from the pericarp of the mangosteen fruit, has been shown to inhibit the growth of tumor cells in various types of cancers. However, the underlying molecular mechanisms are largely unclear. Here, we report that α-mangostin suppressed the viability and epithelial-mesenchymal transition (EMT) of pancreatic cancer cells through inhibition of the PI3K/Akt pathway. Treatment of pancreatic cancer BxPc-3 and Panc-1 cells with α-mangostin resulted in loss of cell viability, accompanied by enhanced cell apoptosis, cell cycle arrest at G1 phase, and decrease of cyclin-D1. Moreover, Transwell and Matrigel invasion assays showed that α-mangostin significantly reduced the migration and invasion of pancreatic cancer cells. Consistent with these results, α-mangostin decreased the expression of MMP-2, MMP-9, N-cadherin, and vimentin and increased the expression of E-cadherin. Furthermore, we found that α-mangostin suppressed the activity of the PI3K/Akt pathway in pancreatic cancer cells as demonstrated by the reduction of the Akt phosphorylation by α-mangostin. Finally, α-mangostin significantly inhibited the growth of BxPc-3 tumor mouse xenografts. Our results suggest that α-mangostin may be potentially used as a novel adjuvant therapy or complementary alternative medicine for the management of pancreatic cancers.
doi:10.1155/2014/546353
PMCID: PMC4000937  PMID: 24812621
18.  Reconstruction of Auto-Tissue-Engineered Lamellar Cornea by Dynamic Culture for Transplantation: A Rabbit Model 
PLoS ONE  2014;9(4):e93012.
To construct an auto-tissue-engineered lamellar cornea (ATELC) for transplantation, based on acellular porcine corneal stroma and autologous corneal limbal explants, a dynamic culture process, which composed of a submersion culture, a perfusion culture and a dynamic air-liquid interface culture, was performed using appropriate parameters. The results showed that the ATELC-Dynamic possessed histological structure and DNA content that were similar to native lamellar cornea (NLC, p>0.05). Compared to NLC, the protein contents of zonula occludens-1, desmocollin-2 and integrin β4 in ATELC-Dynamic reached 93%, 89% and 73%, respectively. The basal cells of ATELC-Dynamic showed a better differentiation phenotype (K3−, P63+, ABCG2+) compared with that of ATELC in static air-lift culture (ATELC-Static, K3+, P63−, ABCG2−). Accordingly, the cell-cloning efficiency of ATELC-Dynamic (9.72±3.5%) was significantly higher than that of ATELC-Static (2.13±1.46%, p<0.05). The levels of trans-epithelial electrical resistance, light transmittance and areal modulus variation in ATELC-Dynamic all reached those of NLC (p>0.05). Rabbit lamellar keratoplasty showed that the barrier function of ATELC-Dynamic was intact, and there were no signs of epithelial shedding or neovascularization. Furthermore, the ATELC-Dynamic group had similar optical properties and wound healing processes compared with the NLC group. Thus, the sequential dynamic culture process that was designed according to corneal physiological characteristics could successfully reconstruct an auto-lamellar cornea with favorable morphological characteristics and satisfactory physiological function.
doi:10.1371/journal.pone.0093012
PMCID: PMC3976280  PMID: 24705327
19.  Characteristic Variation of α-Fetoprotein DNA Nanometer-Range Irradiated by Iodine-125 
Abstract
To obtain the characteristic variation of structure and functional groups of α-fetoprotein (AFP) DNA irradiated by iodine-125(125I), the AFP antisense oligonucleotide labeled with various radioactivity dose 125I was mixed with the AFP DNA in a simulated polymerase chain reaction temperature condition. After the mixtures were irradiated by the 125I from 2 to 72 hours, the mutation of the biogenic conformation and functional groups of the irradiated DNA were investigated using laser Raman spectroscopy. The shifted peak and the decreased intensity of the characteristic Raman spectra were found, which demonstrated that the structure of the phosphodiester linkage was broke, the pyridine and purine bases in DNA emerged and damaged. The model of gene conformation changed from form B to form C spectrum after the nanometer-range irradiation with 125I from 2 to 24 hours. The damage of local pyridine and purine bases gradually increased along with the accumulation of irradiation, and the bases and ribosome were finally dissociated and stacked.
doi:10.1089/cbr.2012.1231
PMCID: PMC3615693  PMID: 23573955
gene therapy; irradiation; radionuclide; Raman spectroscopy
20.  Prognostic Role of Pre-Treatment Serum AFP-L3% in Hepatocellular Carcinoma: Systematic Review and Meta-Analysis 
PLoS ONE  2014;9(1):e87011.
Background
Serum lens culinaris agglutinin-reactive fraction of α-fetoprotein (AFP-L3%) has been widely used for HCC diagnosis and follow-up surveillance as tumor serologic marker. However, the prognostic value of high pre-treatment serum AFP-L3% in patients with hepatocellular carcinoma (HCC) remains controversial. We therefore conduct a meta-analysis to assess the relationship between high pre-treatment serum AFP-L3% and clinical outcome of HCC.
Methods
Eligible studies were identified through systematic literature searches. A meta-analysis of fifteen studies (4,465 patients) was carried out to evaluate the association between high pre-treatment serum AFP-L3% and overall survival (OS) and disease-free survival (DFS) in HCC patients. Sensitivity and subgroup analyses were also conducted in this meta-analysis.
Results
Our analysis results showed that high pre-treatment serum AFP-L3% implied poor OS (HR: 1.65, 95%CI: 1.45–1.89 p<0.00001) and DFS (HR: 1.80, 95% CI: 1.49–2.17 p<0.00001) of HCC. Subgroup analysis revealed that there was association between pre-treatment serum AFP-L3% and endpoint (OS and DFS) in low AFP concentration HCC patients (HR: 1.96, 95% CI: 1.24–3.10, p = 0.004; HR: 2.53, 95% CI: 1.09–5.89, p = 0.03, respectively).
Conclusion
The current evidence suggests that high pre-treatment serum AFP-L3% levels indicated a poor prognosis for patients with HCC and AFP-L3% may have significant prognostic value in HCC patients with low AFP concentration.
doi:10.1371/journal.pone.0087011
PMCID: PMC3907387  PMID: 24498011
21.  Enrichment of human osteosarcoma stem cells based on hTERT transcriptional activity 
Oncotarget  2013;4(12):2326-2338.
Telomerase is crucial for the maintenance of stem/progenitor cells in adult tissues and is detected in most malignant cancers, including osteosarcoma. However, the relationship between telomerase expression and cancer stem cells remains unknown. We observed that sphere-derived osteosarcoma cells had higher telomerase activity, indicating that telomerase activity might be enriched in osteosarcoma stem cells. We sorted subpopulations with high or low telomerase activity (TEL) using hTERT transcriptional promoter-induced green fluorescent protein (GFP). The TELpos cells showed an increased sphere and tumor propagating capacity compared to TELneg cells, and enhanced stem cell-like properties such as invasiveness, metastatic activity and resistance to chemotherapeutic agents both in vitro and in vivo. Furthermore, the telomerase inhibitor MST312 prevented tumorigenic potential both in vitro and in vivo, preferentially targeting the TELpos cells. These data support telomerase inhibition as a potential targeted therapy for osteosarcoma stem-like cells.
PMCID: PMC3926830  PMID: 24334332
Osteosarcoma; Heterogeneity; Cancer stem cells; Telomerase; Metastasis; Drug resistance
22.  Pathway and Mechanism of pH Dependent Human Hemoglobin Tetramer-Dimer-Monomer Dissociations 
PLoS ONE  2013;8(11):e81708.
Hemoglobin dissociation is of great interest in protein process and clinical medicine as well as in artificial blood research. However, the pathway and mechanisms of pH-dependent human Hb dissociation are not clear, whether Hb would really dissociate into monomers is still a question. Therefore, we have conducted a multi-technique investigation on the structure and function of human Hb versus pH. Here we demonstrate that tetramer hemoglobin can easily dissociate into dimer in abnormal pH and the tetramer → dimer dissociation is reversible if pH returns to normal physiological value. When the environmental pH becomes more acidic (<6.5) or alkaline (>8.0), Hb can further dissociate from dimer to monomer. The proportion of monomers increases while the fraction of dimers decreases as pH declines from 6.2 to 5.4. The dimer → monomer dissociation is accompanied with series changes of protein structure thus it is an irreversible process. The structural changes in the dissociated Hbs result in some loss of their functions. Both the Hb dimer and monomer cannot adequately carry and release oxygen to the tissues in circulation. These findings provide a comprehensive understanding on the pH-dependent protein transitions of human Hb, give guideline to explain complex protein processes and the means to control protein dissociation or re-association reaction. They are also of practical value in clinical medicine, blood preservation and blood substitute development.
doi:10.1371/journal.pone.0081708
PMCID: PMC3842943  PMID: 24312337
23.  hTERT promoter activity identifies osteosarcoma cells with increased EMT characteristics 
Oncology Letters  2013;7(1):239-244.
Epithelial-mesenchymal transition (EMT) is a critical step in order for epithelial-derived malignancies to metastasize, however, its role in mesenchymal-derived tumors, i.e., osteosarcoma, remains unclear. Cancer stem cells (CSCs) are enriched with cells that undergo EMT. The activity of telomerase is maintained in normal stem cells and a number of malignant tumors. The current study observed the heterogeneity of telomerase activity among individual osteosarcoma cells. We hypothesized that telomerase-positive (TELpos) cells are enriched for stem cell-like and EMT properties. A human telomerase reverse transcriptase (hTERT) promoter-reporter was applied to assess the telomerase activity of individual MG63 osteosarcoma cells and sort them into TELpos and telomerase-negative (TELneg) subpopulations. It was found that the TELpos cells exhibited an enhanced ability to form sarcospheres in vitro. In addition, TELpos cells exhibited a higher expression of vimentin, accompanied by an increased long/short axis ratio. A panel of EMT-related genes was evaluated by quantitative PCR and western blot analysis, and were found to be significantly upregulated in TELpos cells. Next, the in vitro migration capacity was examined by Transwell assay, which confirmed that TELpos cells are more prone to migration (2.6 fold). The results of the present study support the concept that EMT also applies to mesenchymal-derived osteosarcoma and draws a connection between telomerase and EMT characteristics.
doi:10.3892/ol.2013.1692
PMCID: PMC3861599  PMID: 24348856
osteosarcoma; human telomerase reverse transcriptase; telomerase; epithelial-mesenchymal transition
24.  Diagnosis and treatment of hepatic tuberculosis: report of five cases and review of literature 
Hepatic tuberculosis is uncommon, lack of specific clinical manifestations and imaging features, so it can easily be misdiagnosed in clinical. Herein, we discuss variety of its forms and summarize the diagnosis and treatment of hepatic tuberculosis in this paper. Five cases of hepatic tuberculosis are described. The diagnosis, treatment and outcome of the patients are discussed. Image examination associated with image-guided fine needle aspiration biopsy is the best diagnostic method. In our center, three patients underwent needle biopsy and confirmed hepatic tuberculosis. In addition, two patients preoperative misdiagnosed as cholangiocarcinoma were confirmed hepatic tuberculosis by postoperative pathology. Three patients underwent surgical procedures along with anti-tubercular drug therapy, two patients received only anti-tubercular drug therapy. The renal post-transplantation patient with hepatic tuberculosis eventually died of multiple organ failure (MODS). The other four patients were followed for 48~120 months, yielding no recurrence of hepatic tuberculosis. In conclusion, hepatic tuberculosis usually associated with atypical clinical manifestations. Image examination associated with image-guided fine needle aspiration biopsy is the best diagnostic method. Anti-TB treatment is effective in most of cases. However, if there are indications for surgery or difficult to diagnose, surgical procedures along with anti-tubercular drug therapy could be adopted.
PMCID: PMC3798224  PMID: 24179582
Liver mass; tuberculoma; tuberculosis; TB; anti-TB
25.  Pancreaticoduodenectomy Combined with Vascular Resection and Reconstruction for Patients with Locally Advanced Pancreatic Cancer: A Multicenter, Retrospective Analysis 
PLoS ONE  2013;8(8):e70340.
Objective
The aim of this study was to present the therapeutic outcome of patients with locally advanced pancreatic cancer treated with pancreatoduodenectomy combined with vascular resection and reconstruction in addition to highlighting the mortality/morbidity and main prognostic factors associated with this treatment.
Materials and Methods
We retrospectively analyzed the clinical and pathological data of a total of 566 pancreatic cancer patients who were treated with PD from five teaching hospitals during the period of December 2006–December 2011. This study included 119 (21.0%) patients treated with PD combined with vascular resection and reconstruction. We performed a detailed statistical analysis of various factors, including postoperative complications, operative mortality, survival rate, operative time, pathological type, and lymph node metastasis.
Results
The median survival time of the 119 cases that received PD combined with vascular resection was 13.3 months, and the 1-, 2-, and 3-year survival rates were 30.3%, 14.1%, and 8.1%, respectively. The postoperative complication incidence was 23.5%, and the mortality rate was 6.7%. For the combined vascular resection group, complications occurred in 28 cases (23.5%). For the group without vascular resection, complications occurred in 37 cases (8.2%). There was significant difference between the two groups (p = 0.001). The degree of tumor differentiation and the occurrence of complications after surgery were independent prognostic factors that determined the patients’ long-term survival.
Conclusions
Compared with PD without vascular resection, PD combined with vascular resection and reconstruction increased the incidence of postoperative complications. However, PD combined with vascular resection and reconstruction could achieve the complete removal of tumors without significantly increasing the mortality rate, and the median survival time was higher than that of patients who underwent palliative treatment. In addition, the two independent factors affecting the postoperative survival time were the degree of tumor differentiation and the presence or absence of postoperative complications.
doi:10.1371/journal.pone.0070340
PMCID: PMC3732270  PMID: 23936411

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