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Neuro-Oncology  2014;16(Suppl 3):iii16.
BACKGROUND: The nuclear factor-kB (NF-kB) family of transcriptional regulators are central mediators of the cellular inflammatory response. Although constitutive NF-kB signaling is present in most human tumours, mutations in pathway members are rare, complicating efforts to understand and block aberrant NF-kB activity in cancer. METHODS: To identify additional genetic alterations that drive ependymoma, we sequenced the whole genomes (WGS) of 41 tumours and matched normal blood, and the transcriptomes (RNAseq) of 77 tumours. The transforming significance of alterations were tested in mouse NSCs that we showed previously to be cells of origin of ependymoma. RESULTS: Here, we show that more than two thirds of supratentorial ependymomas contain oncogenic fusions between RELA, the principal effector of canonical NF-kB signalling, and an uncharacterized gene, C11orf95. In each case, C11orf95-RELA fusions resulted from chromothripsis involving chromosome 11q13.1. C11orf95-RELA fusion proteins translocated spontaneously to the nucleus to activate NF-kB target genes, and rapidly transformed neural stem cells—the cell of origin of ependymoma—to form these tumours in mice. CONCLUSIONS: Our data identify the first highly recurrent genetic alteration of RELA in human cancer, and the C11orf95-RELA fusion protein as a potential therapeutic target in supratentorial ependymoma. SECONDARY CATEGORY: Neuropathology & Tumor Biomarkers.
PMCID: PMC4144525
2.  High USP22 expression indicates poor prognosis in hepatocellular carcinoma 
Oncotarget  2015;6(14):12654-12667.
Ubiquitin-specific protease 22 (USP22) removes ubiquitin from histones, thus regulating gene transcription. The expression frequency and expression levels of USP22 were significantly higher in hepatocellular carcinoma (HCC) than in normal liver tissues. High USP22 expression in HCC was significantly correlated with clinical stage and tumor grade. Kaplan-Meier analysis showed that elevated USP22 expression predicted poorer overall survival and recurrence-free survival. High USP22 expression was also associated with shortened survival time in patients at advanced tumor stages and with high grade HCC. Multivariate analyses revealed that USP22 expression is an independent prognostic parameter in HCC. These findings provide evidence that high USP22 expression might be important in tumor progression and serves as an independent molecular marker for poor HCC prognosis. Thus, USP22 overexpression identifies patients at high risk and represents a novel therapeutic molecular target for this tumor.
PMCID: PMC4494964  PMID: 25909224
hepatocellular carcinoma; ubiquitin-specific protease 22; prognosis; cancer biomarker
3.  JARID1B promotes metastasis and epithelial-mesenchymal transition via PTEN/AKT signaling in hepatocellular carcinoma cells 
Oncotarget  2015;6(14):12723-12739.
JARID1B is a member of the family of JmjC domain-containing proteins that removes methyl residues from methylated lysine 4 on histone H3 lysine 4 (H3K4). JARID1B has been proposed as an oncogene in many types of tumors; however, its role and underlying mechanisms in hepatocellular carcinoma (HCC) remain unknown. Here we show that JARID1B is elevated in HCC and its expression level is positively correlated with metastasis. In addition Kaplan-Meier survival analysis showed that high expression of JARID1B was associated with decreased overall survival of HCC patients. Overexpression of JARID1B in HCC cells increased proliferation, epithelial-mesenchymal transition, migration and invasion in vitro, and enhanced tumorigenic and metastatic capacities in vivo. In contrast, silencing JARID1B in aggressive and invasive HCC cells inhibited these processes. Mechanistically, we found JARID1B exerts its function through modulation of H3K4me3 at the PTEN gene promoter, which was associated with inactive PTEN transcription. PTEN overexpression blocked JARID1B-driven proliferation, EMT, and metastasis. Our results, for the first time, portray a pivotal role of JARID1B in stimulating metastatic behaviors of HCC cells. Targeting JARID1B may thus be a useful strategy to impede HCC cell invasion and metastasis.
PMCID: PMC4494969  PMID: 25909289
JARID1B; metastasis; epithelial-mesenchymal transition; invasion; PTEN
4.  Daytime Land Surface Temperature Extraction from MODIS Thermal Infrared Data under Cirrus Clouds 
Sensors (Basel, Switzerland)  2015;15(5):9942-9961.
Simulated data showed that cirrus clouds could lead to a maximum land surface temperature (LST) retrieval error of 11.0 K when using the generalized split-window (GSW) algorithm with a cirrus optical depth (COD) at 0.55 μm of 0.4 and in nadir view. A correction term in the COD linear function was added to the GSW algorithm to extend the GSW algorithm to cirrus cloudy conditions. The COD was acquired by a look up table of the isolated cirrus bidirectional reflectance at 0.55 μm. Additionally, the slope k of the linear function was expressed as a multiple linear model of the top of the atmospheric brightness temperatures of MODIS channels 31–34 and as the difference between split-window channel emissivities. The simulated data showed that the LST error could be reduced from 11.0 to 2.2 K. The sensitivity analysis indicated that the total errors from all the uncertainties of input parameters, extension algorithm accuracy, and GSW algorithm accuracy were less than 2.5 K in nadir view. Finally, the Great Lakes surface water temperatures measured by buoys showed that the retrieval accuracy of the GSW algorithm was improved by at least 1.5 K using the proposed extension algorithm for cirrus skies.
PMCID: PMC4481960  PMID: 25928059
cirrus clouds; error correction; generalized split-window algorithm; land surface temperature retrieval; MODIS
5.  Comparison of two self-assembled macromolecular prodrug micelles with different conjugate positions of SN38 for enhancing antitumor activity 
7-Ethyl-10-hydroxycamptothecin (SN38), an active metabolite of irinotecan (CPT-11), is a remarkably potent antitumor agent. The clinical application of SN38 has been extremely restricted by its insolubility in water. In this study, we successfully synthesized two macromolecular prodrugs of SN38 with different conjugate positions (chitosan-(C10-OH)SN38 and chitosan-(C20-OH)SN38) to improve the water solubility and antitumor activity of SN38. These prodrugs can self-assemble into micelles in aqueous medium. The particle size, morphology, zeta potential, and in vitro drug release of SN38 and its derivatives, as well as their cytotoxicity, pharmacokinetics, and in vivo antitumor activity in a xenograft BALB/c mouse model were studied. In vitro, chitosan-(C10-OH)SN38 (CS-(10s)SN38) and chitosan-(C20-OH) SN38 (CS-(20s)SN38) were 13.3- and 25.9-fold more potent than CPT-11 in the murine colon adenocarcinoma cell line CT26, respectively. The area under the curve (AUC)0–24 of SN38 after intravenously administering CS-(10s)SN38 and CS-(20s)SN38 to Sprague Dawley rats was greatly improved when compared with CPT-11 (both P<0.01). A larger AUC0–24 of CS-(20s)SN38 was observed when compared to CS-(10s)SN38 (P<0.05). Both of the novel self-assembled chitosan-SN38 prodrugs demonstrated superior anticancer activity to CPT-11 in the CT26 xenograft BALB/c mouse model. We have also investigated the differences between these macromolecular prodrug micelles with regards to enhancing the antitumor activity of SN38. CS-(20s)SN38 exhibited better in vivo antitumor activity than CS-(10s)SN38 at a dose of 2.5 mg/kg (P<0.05). In conclusion, both macromolecular prodrug micelles improved the in vivo conversion rate and antitumor activity of SN38, but the prodrug in which C20-OH was conjugated to macromolecular materials could be a more promising platform for SN38 delivery.
PMCID: PMC4376263  PMID: 25848251
self-assembled prodrug micelles; in vitro cytotoxicity; pharmacokinetics; in vivo antitumor activity
6.  Effects of high-fat diet on 1,2-dimethylhydrazine-induced aberrant crypt foci and colorectal tumours in rats 
Biomedical Reports  2015;3(3):289-294.
Obesity is one of the leading causes of numerous types of cancer. The present study investigated the impact of a high-fat diet on 1,2-dimethylhydrazine (DMH)-induced colorectal cancer (CRC) in F344 rats. A total of 16 male F344 rats aged 4 weeks were randomly divided into two groups (8 rats/group). Rats in group A were fed a basal diet with a moderate fat (MF) content, while rats in group B were fed a high-fat diet. Upon reaching 5 weeks of age, the rats were injected subcutaneously with DMH (20 mg/kg body weight). DMH was administered once a week for 8 consecutive weeks. All the rats were sacrificed 34 weeks after the first DMH injection and dissected to obtain samples of colorectal tissues. The tissues were examined under a microscope for the presence of aberrant crypt foci (ACFs) and subjected to histopathological analysis. The results showed that at the end of the 34-week experiment, body weights and visceral fat levels were significantly higher in the high-fat diet group compared to the basal diet group. In addition, the incidences of colorectal ACF, adenoma and adenocarcinoma were markedly elevated in the high-fat diet group compared to the basal diet group. These results indicate that the consumption of a high-fat diet promotes the development and progression of CRC and the control of fat intake may prevent CRC.
PMCID: PMC4467215  PMID: 26137224
high-fat diet; antitumour; colorectal cancer; F344 rats
7.  Mechanisms of Gefitinib-mediated reversal of tamoxifen resistance in MCF-7 breast cancer cells by inducing ERα re-expression 
Scientific Reports  2015;5:7835.
Estrogen receptor (ER)-positive breast cancer patients may turn ER-negative and develop acquired drug resistance, which compromises the efficacy of endocrine therapy. By investigating the phenomenon that gefitinib can re-sensitise tamoxifen (TAM)-resistant MCF-7 breast cancer cells (MCF-7/TAM) to TAM, the present study verified that gefitinib could reverse the acquired drug resistance in endocrine therapy and further explored the underlying mechanism.ERα-negative MCF-7/TAM cells were established. Upon treating the cells with gefitinib, the mRNA and protein levels of ERα and ERβ, as well as the expression of molecules involved in the MAPK pathway, were examined using the RT-PCR and immunocytochemistry. The RT-PCR results showed that the mRNA levels of ERα and ERβ in MCF-7/TAM cells were up-regulated following gefitinib treatment; specifically, ERα was re-expressed, and ERβ expression was up-regulated. The expression of molecules involved in the MAPK pathway, including RAS, MEK1/2, and p-ERK1/2, in MCF-7/TAM cells was significantly up-regulated, compared with MCF-7 cells. After the gefitinib treatment, the expression levels of MEK1/2 and p-ERK1/2 were significantly down-regulated. ERα loss is the primary cause for TAM resistance. Gefitinib reverses TAM resistance primarily by up-regulating the ERα mRNA level and inducing the re-expression of ERα. The MAPK pathway plays a key role in ERα re-expression.
PMCID: PMC4314651  PMID: 25644501
8.  KDM5B is overexpressed in gastric cancer and is required for gastric cancer cell proliferation and metastasis 
Epigenetic alterations such as aberrant expression of histone-modifying enzymes have been implicated in tumorigenesis. KDM5B (also known as JARID1B) is a newly identified histone demethylase that regulates chromatin structure or gene expression by removing methyl residues from trimethylated lysine 4 on histone H3. Recent observations have shown oncogenic activity of KDM5B. However, the role of KDM5B in gastric cancer carcinogenesis remains unclear. In this study, we aimed to investigate the role of KDM5B in gastric cancer. Immunohistochemical analysis, western blotting, and qRT-PCR were used to measure the levels of KDM5B in gastric cancer cell lines, 45 pairs of gastric cancer tissues and the adjacent nonneoplastic tissues. KDM5B and shKDM5B were transfected into gastric cancer cells to investigate its role on regulating cell proliferation which was measured by MTT and colony formation assay. Cell’s migration and invasion were measured by Transwell and Matrigel analysis in vitro. PCNA expression was measured by immunofluorescence staining and immunohistochemical analysis. The in vivo tumorigenesis and metastasis assays were performed in SCID mice. In clinical gastric cancer samples, we found that KDM5B expression was significantly up-regulated in cancer lesions compared with paired normal gastric tissues. By silencing or overexpressing KDM5B in gastric cancer cells, we found that KDM5B could promote cell growth and metastasis in vitro. An in vivo assay showed that KDM5B not only dramatically promoted gastric cancer cell xenograft formation and growth but also promoted gastric cancer cell metastasis in a liver metastasis model. Moreover, we demonstrated that KDM5B promoted gastric cancer metastasis via regulation of the Akt pathway. Our study provided evidence that KDM5B functions as a novel tumor oncogene in gastric cancer and may be a potential therapeutic target for gastric cancer management.
PMCID: PMC4300698  PMID: 25628922
KDM5B; gastric cancer; proliferation; metastasis
9.  Metastasis of the liver with a granulosa cell tumor of the ovary: A case report 
Oncology Letters  2014;9(2):816-818.
The present study describes the case of a 62 year-old female patient with a metastatic tumor in the right hemi-liver of >25 cm in diameter, who presented to The Affiliated Hospital of Guilin Medical University (Guangxi, China) with acute abdominal pain and severe malnutrition. Radical surgery was performed to remove the tumor by open surgery. A biopsy was not performed prior to the surgery, so the tumor was diagnosed as end-stage primary liver cancer (PLC) based solely on the character and appearance of the tumor on computed tomography prior to surgery. However, subsequent to the surgery, upon analysis by the Department of Pathology, the mass was identified as an ovarian granulosa cell tumor (GCT). These tumors occur rarely, representing only 2–3% of all ovarian tumors, and are well known for late recurrences, with an incidence of 25–30%. As metastasis of the liver with GCT is extremely rare and the data available on the subject is limited by the small number of studies, and due to the absence of a biopsy report prior to surgery, the patient was initially misdiagnosed with PLC. However, despite this misdiagnosis, a good result was obtained, as the patient was later diagnosed with GCT following a detailed pathological examination and was treated with rational therapy. The performance status and quality of life were significantly improved, and the patient remains disease-free at one year post-surgery.
PMCID: PMC4301485  PMID: 25621056
metastasis; liver; granulosa cell tumor; ovary
10.  Aberrant Upregulation of 14-3-3σ and EZH2 Expression Serves as an Inferior Prognostic Biomarker for Hepatocellular Carcinoma 
PLoS ONE  2014;9(9):e107251.
Hepatocellular carcinoma (HCC) is the fifth most common malignancy in the world. It is of important significance to find biomarkers for the prognostic monitoring of HCC. The 14-3-3σ and EZH2 proteins are involved in cell cycle regulation and epigenetic silencing. We herein examined the significance of 14-3-3 σ and EZH2 in HCC (n = 167) by immunohistochemistry, RT-PCR and qRT-PCR. The correlation between 14-3-3σ and EZH2 expression and patients' clinicopathologic features were examined, as was the correlation between 14-3-3σ and EZH2 expression and the prognosis of HCC patients. We found that 14-3-3σ and EZH2 were highly expressed in HCC (71% and 90%), the expression of EZH2, but not 14-3-3σ, is associated with vascular invasion and tumor differentiation (p<0.01). The coexistence of 14-3-3σ and EZH2 overexpression is associated with a relatively unfavorable prognosis (p<0.01), suggesting that aberrant upregulation of 14-3-3σ and EZH2 expression serves as an inferior prognostic biomarker for HCC.
PMCID: PMC4165773  PMID: 25226601
11.  C11orf95-RELA fusions drive oncogenic NF-κB signaling in ependymoma 
Nature  2014;506(7489):451-455.
The nuclear factor-κB (NF-κB) family of transcriptional regulators are central mediators of the cellular inflammatory response. Although constitutive NF-κB signaling is present in most human tumours, mutations in pathway members are rare, complicating efforts to understand and block aberrant NF-κB activity in cancer. Here, we show that more than two thirds of supratentorial ependymomas contain oncogenic fusions between RELA, the principal effector of canonical NF-κB signalling, and an uncharacterized gene, C11orf95. In each case, C11orf95-RELA fusions resulted from chromothripsis involving chromosome 11q13.1. C11orf95-RELA fusion proteins translocated spontaneously to the nucleus to activate NF-κB target genes, and rapidly transformed neural stem cells—the cell of origin of ependymoma—to form these tumours in mice. Our data identify the first highly recurrent genetic alteration of RELA in human cancer, and the C11orf95-RELA fusion protein as a potential therapeutic target in supratentorial ependymoma.
PMCID: PMC4050669  PMID: 24553141
12.  Elimination of the formation of biofilm in industrial pipes using enzyme cleaning technique 
MethodsX  2014;1:130-136.
Graphical abstract
Currently, there is a growing demand in how to eliminate the biofilm formed in industrial pipelines, especially in food, fermentation, and water treatment industry. However, the traditional techniques for CIP (cleaning in place) are usually ineffective, superficial, halfway, and do not clean or sterilize microbes located in the inner layers of the biofilm. A recent strategy for removing the biofilm in pipes is employing enzymes to clean it in the circulating water system under an optimal condition. However, how to operate and control the whole cleaning process is difficult. Here, we will introduce the strategy of enzyme cleaning to make it more appropriated and effective.•A modification of CIP method is proposed for higher efficiency by using N-acetylmuramide glycanohydrolase as catalysts whose optimal pH and temperature is 10 ± 1 and 45 ± 2 °C, respectively.•The initial efficiency of enzyme cleaning was evaluated by testing the content of ATP in water sample using Clean-Trace™ (3M Corporation).•Lastly, the terminal water was tested with SLYM-BART™ (HACH Corporation) to find out whether there were biofilm-forming bacteria, such as Pseudomonas aeruginosa (Lakretz et al. (2011) [1]), Pseudomonas fluorescens (O’Toole and Kolter (1998) [2]), iron bacterium, etc.
PMCID: PMC4472951  PMID: 26150944
Biofilm; Enzyme cleaning; Biofilm-forming bacteria; CIP (cleaning in place)
13.  Clinicopathological correlation and prognostic significance of sonic hedgehog protein overexpression in human gastric cancer 
Objectives: This study investigated the expression of Sonic Hedgehog (Shh) protein in gastric cancer, and correlated it with clinicopathological parameters. The prognostic significance of Shh protein was analyzed. Methods: Shh protein expression was evaluated in 113 cases of gastric cancer and 60 cases of normal gastric mucosa. The immunoreactivity was scored semi quantitatively as: 0 = absent; 1 = weak; 2 = moderate; and 3 = strong. All cases were further classified into two groups, namely non-overexpression group with score 0 or 1, and overexpression group with score 2 or 3. The overexpression of Shh protein was correlated with clinicopathological parameters. Survival analysis was then performed to determine the Shh protein prognostic significance in gastric cancer. Results: In immunohistochemistry study, nineteen (31.7%) normal gastric mucosa revealed Shh protein overexpression, while eighty-one (71.7%) gastric cancer revealed overexpression. The expression of Shh protein were significantly higher in gastric cancer tissues than in normal gastric mucosa (P < 0.001), which was statistically correlated with age (P = 0.006), tumor differentiation (P < 0.001), depth of invasion (P = 0.042), pathologic staging (P = 0.017), and nodal metastasis (P = 0.019). We found no significant difference in both overall and disease free survival rates between Shh overexpression and non-expression groups P = 0.168 and 0.071). However, Shh overexpression emerged as a significant independent prognostic factor in multivariate Cox regression analysis (hazard ratio 1.187, P = 0.041). Conclusions: Shh protein expression is upregulated and is statistically correlated with age, tumor differentiation, depth of invasion, pathologic staging, and nodal metastasis. The Shh protein overexpression is a significant independent prognostic factor in multivariate Cox regression analysis in gastric cancer.
PMCID: PMC4152078  PMID: 25197388
Sonic hedgehog; pathology; prognosis; gastric cancer
14.  Expression of Recombinant Human FADD, Preparation of Its Polyclonal Antiserum and the Application in Immunoassays 
The wild-type human Fas-associated death domain (FADD) protein was expressed as a His-tag fusion protein in Escherichia coli. Recombinant FADD proteins were purified under the denatured condition. After denatured protein purification, it was refolded and obtained at a yield of about 23 mg/L. Purified FADD exhibited as a homogenous band corresponding to the molecular weight of 31 kDa. Immunization of rabbits against the refolded FADD protein was allowed the production of high titre polyclonal antiserum. This new polyclonal antibody could recognize recombinant FADD protein in Western blot. Immunoreactivity was also observed in immunofluorescence assay. The low cost polyclonal antiserum was applicable to extensive detection of FADD in various immunoassays.
PMCID: PMC4073656  PMID: 19118514
FADD; His-tag fusion protein; polyclonal antibody; immunofluorescence assay
15.  H2O2 Accumulation Mediates Differentiation Capacity Alteration, But Not Proliferative Decline, in Senescent Human Fetal Mesenchymal Stem Cells 
Antioxidants & Redox Signaling  2013;18(15):1895-1905.
Aims: Mesenchymal stem cells (MSCs) with multilineage differentiation capacity and immunomodulatory properties are novel sources for cell therapy. However, in vitro expansion of these rare somatic stem cells leads to senescence, resulting in declines of differentiation and proliferative capacities. We therefore investigated the mechanisms mediating senescence in human fetal MSCs termed placenta-derived multipotent cells (PDMCs). Results: Long-term cultured PDMCs underwent senescence, with increased levels of hydrogen peroxide (H2O2; a reactive oxygen species), positive β-galactosidase staining, decreased sirtuin-1 expression, increased p21 expression, and cell cycle arrest at the G0/G1 phase. Senescent PDMCs also showed decreased osteogenic capacity. Mechanistically, increased p21 expression and proliferative decline were not due to elevated H2O2 levels nor mediated by p53. Instead, inhibition of protein kinase C (PKC)-α and -β in senescent PDMCs decreased p21 expression and reversed cell cycle arrest. H2O2 was involved in the alteration of differentiation potential, since scavenging of H2O2 restored expression of c-MAF, an osteogenic and age-sensitive transcription factor, and osteogenic capacity in senescent PDMCs. Innovation: Our findings not only show the effects of senescence on MSCs, but also reveal mechanisms involved in mediating decreased proliferation and differentiation capacity. Moreover, targeting increased levels of H2O2 associated with senescence may reverse the decreased osteogenic capacity of senescent MSCs. Conclusion: Our study suggests that the two biological consequences of senescence, differentiation alteration, and proliferative decline, in fetal MSCs are distinctly regulated by the H2O2-c-MAF and PKC-p21 pathways, respectively. Antioxid. Redox Signal. 18, 1895–1905.
PMCID: PMC3624695  PMID: 23088254
16.  Electronic polarization stabilizes tertiary structure prediction of HP-36 
Journal of Molecular Modeling  2014;20(4):2195.
Molecular dynamic (MD) simulations with both implicit and explicit solvent models have been carried out to study the folding dynamics of HP-36 protein. Starting from the extended conformation, the secondary structure of all three helices in HP-36 was formed in about 50 ns and remained stable in the remaining simulation. However, the formation of the tertiary structure was difficult. Although some intermediates were close to the native structure, the overall conformation was not stable. Further analysis revealed that the large structure fluctuation of loop and hydrophobic core regions was devoted mostly to the instability of the structure during MD simulation. The backbone root-mean-square deviation (RMSD) of the loop and hydrophobic core regions showed strong correlation with the backbone RMSD of the whole protein. The free energy landscape indicated that the distribution of main chain torsions in loop and turn regions was far away from the native state. Starting from an intermediate structure extracted from the initial AMBER simulation, HP-36 was found to generally fold to the native state under the dynamically adjusted polarized protein-specific charge (DPPC) simulation, while the peptide did not fold into the native structure when AMBER force filed was used. The two best folded structures were extracted and taken into further simulations in water employing AMBER03 charge and DPPC for 25 ns. Result showed that introducing polarization effect into interacting potential could stabilize the near-native protein structure.
PMCID: PMC3996369  PMID: 24715046
Molecular dynamics; Polarization effect; Protein folding; Solvent model
17.  Dragon's blood and its extracts attenuate radiation-induced oxidative stress in mice 
Journal of Radiation Research  2014;55(4):699-706.
Dragon's blood (DB) possesses great medicinal values due to the presence of several phenolic compounds. This study was designed to investigate the effects of DB and its extracts (DBEs) on oxidative stress in mice exposed to whole body 60Co-γ irradiation (4 Gy). DB and DBEs were intragastrically administered to mice for 5 d prior to radiation. The antioxidant activities, including malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT) and glutathione (GSH) levels in liver and spleen were measured using kits. Furthermore, DB and DBE effects were determined by organ indices and histology of liver and spleen. Our results indicated that the DB and DBE-treated groups showed a significant decrease (P < 0.05) in levels of MDA in liver and spleen compared with the irradiation-only group. Moreover, the activity of SOD, CAT and the level of GSH in liver and spleen tissue were enhanced significantly (P < 0.05) in the DB and DBE groups. DB and DBE also had a significant effect on the recovery of thymus indices. The histological observations of groups having treatment with DB and DBE indicated significant reduction in the radiation-induced damage to the liver and spleen, together with improvement in the morphology of the liver and spleen. These results suggest that DB and DBE treatment prevents radiation-induced oxidative stress injury and restores antioxidant status and histopathological changes in the liver and spleen, but there is need for further study to explore the precise molecular mechanism and strategy for optimal practical application of DB and DBE.
PMCID: PMC4100005  PMID: 24634306
dragon's blood; radioprotective effects; irradiation; oxidative stress
18.  Highly efficient ionization of phosphopeptides at low pH by desorption electrospray ionization mass spectrometry† 
The Analyst  2013;138(5):1321-1324.
A fast and novel strategy for efficient ionization of phosphopeptides in mixtures is reported, in which the sample is acidified to low pH to suppress the deprotonation of phosphate groups and then followed by direct analysis using liquid sample desorption electrospray ionization mass spectrometry (DESI-MS).
PMCID: PMC3938891  PMID: 23338759
19.  Characterization of T cell phenotype and function in a double transgenic (collagen-specific TCR/HLA-DR1) humanized model of arthritis 
T cells orchestrate joint inflammation in rheumatoid arthritis (RA), yet they are difficult to study due to the small numbers of antigen-specific cells. The goal of this study was to characterize a new humanized model of autoimmune arthritis and to describe the phenotypic and functional changes that occur in autoimmune T cells following the induction of pathological events.
We developed a double transgenic mouse containing both the HLA-DR1 transgene and an HLA-DR1-restricted collagen-specific TCR in order to obtain large numbers of antigen-specific T cells that can be used for immunologic studies.
In vitro, CII-specific T cells from this mouse proliferated vigorously in response to the CII immunodominant peptide A2 and the cells altered their phenotype to become predominately CD62Llow and CD44high “activated” T cells. The response was accompanied by the production of Th1, Th2, and Th17-type cytokines. Following immunization with bovine CII/CFA, these mice develop an accelerated arthritis compared to single transgenic HLA-DR1 mice. On the other hand, when the mice were treated orally with the analog peptide A12, (a suppressive analog of collagen we have previously described), arthritis was significantly suppressed, despite the fact that >90% of the CD4+ T cells express the TCR Tg. In GALT tissues taken from the A12-treated mice, IL-2, IFN-γ, and IL-17 production to the autoimmune collagen determinant dropped while high levels of IL-10 and IL-4 were produced.
We have developed a humanized model of autoimmune arthritis that will be useful for the study of T cell directed therapies as well as T cell mediated mechanisms of autoimmune diseases.
PMCID: PMC3978884  PMID: 24405551
20.  Annexin V-TRAIL fusion protein is a more sensitive and potent apoptotic inducer for cancer therapy 
Scientific Reports  2013;3:3565.
The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising cancer therapeutic agent, which kills cancer cells selectively, while leaving normal cells unharmed. However, the emerging resistance of tumor cells and patients to TRAIL-induced apoptosis limits its further application. In this study, we developed a chimeric protein Annexin V-TRAIL (designated as TP8) with higher efficacy than TRAIL both in vitro and in vivo. In vitro, the EC50 of TP8 on a series of tumor cells was much lower than wild-type TRAIL. Annexin V provided this recombinant protein with higher efficacy, while leaving tumor specificity of TRAIL unchanged since TP8 had no effects on normal cells. In vivo, TP8 effectively suppressed tumor growth and prolonged tumor doubling time and tumor growth delay time in mouse xenografts involving multiple cancer cell types including A549, Colo205 and Bel7402. This study provides a new rational strategy to treat TRAIL-resistant cancers.
PMCID: PMC3868960  PMID: 24356445
21.  Dynamics of Intracellular Polymers in Enhanced Biological Phosphorus Removal Processes under Different Organic Carbon Concentrations 
BioMed Research International  2013;2013:761082.
Enhanced biological phosphorus removal (EBPR) may deteriorate or fail during low organic carbon loading periods. Polyphosphate accumulating organisms (PAOs) in EBPR were acclimated under both high and low organic carbon conditions, and then dynamics of polymers in typical cycles, anaerobic conditions with excess organic carbons, and endogenous respiration conditions were examined. After long-term acclimation, it was found that organic loading rates did not affect the yield of PAOs and the applied low organic carbon concentrations were advantageous for the enrichment of PAOs. A low influent organic carbon concentration induced a high production of extracellular carbohydrate. During both anaerobic and aerobic endogenous respirations, when glycogen decreased to around 80 ± 10 mg C per gram of volatile suspended solids, PAOs began to utilize polyphosphate significantly. Regressed by the first-order reaction model, glycogen possessed the highest degradation rate and then was followed by polyphosphate, while biomass decay had the lowest degradation rate.
PMCID: PMC3867947  PMID: 24381942
22.  Whole-genome sequencing identifies genetic alterations in pediatric low-grade gliomas 
Nature genetics  2013;45(6):602-612.
The commonest pediatric brain tumors are low-grade gliomas (LGGs). We utilized whole genome sequencing to discover multiple novel genetic alterations involving BRAF, RAF1, FGFR1, MYB, MYBL1 and genes with histone-related functions, including H3F3A and ATRX, in 39 LGGs and low-grade glioneuronal tumors (LGGNTs). Only a single non-silent somatic alteration was detected in 24/39 (62%) tumors. Intragenic duplications of the FGFR1 tyrosine kinase domain (TKD) and rearrangements of MYB were recurrent and mutually exclusive in 53% of grade II diffuse LGGs. Transplantation of Trp53-null neonatal astrocytes containing TKD-duplicated FGFR1 into brains of nude mice generated high-grade astrocytomas with short latency and 100% penetrance. TKD-duplicated FGFR1 induced FGFR1 autophosphorylation and upregulation of the MAPK/ERK and PI3K pathways, which could be blocked by specific inhibitors. Focusing on the therapeutically challenging diffuse LGGs, our study of 151 tumors has discovered genetic alterations and potential therapeutic targets across the entire range of pediatric LGGs/LGGNTs.
PMCID: PMC3727232  PMID: 23583981
23.  Aberrant Expression of Cx43 Is Associated with the Peritoneal Metastasis of Gastric Cancer and Cx43-Mediated Gap Junction Enhances Gastric Cancer Cell Diapedesis from Peritoneal Mesothelium 
PLoS ONE  2013;8(9):e74527.
The process of peritoneal metastasis involves the diapedesis of intra-abdominal exfoliated gastric cancer cells through the mesothelial cell monolayers; however, the related molecular mechanisms for this process are still unclear. Heterocellular gap-junctional intercellular communication (GJIC) between gastric cancer cells and mesothelial cells may play an active role during diapedesis. In this study we detected the expression of connexin 43 (Cx43) in primary gastric cancer tissues, intra-abdominal exfoliated cancer cells, and matched metastatic peritoneal tissues. We found that the expression of Cx43 in primary gastric cancer tissues was significantly decreased; the intra-abdominal exfoliated cancer cells and matched metastatic peritoneal tissues exhibited increasing expression compared with primary gastric cancer tissues. BGC-823 and SGC-7901 human gastric cancer cells were engineered to express Cx43 or Cx43T154A (a mutant protein that only couples gap junctions but provides no intercellular communication) and were co-cultured with human peritoneal mesothelial cells (HPMCs). Heterocellular GJIC and diapedesis through HPMC monolayers on matrigel-coated coverslips were investigated. We found that BGC-823 and SGC-7901 gastric cancer cells expressing Cx43 formed functional heterocellular gap junctions with HPMC monolayers within one hour. A significant increase in diapedesis was observed in engineered Cx43-expressing cells compared with Cx43T154A and control group cells, which suggested that the observed upregulation of diapedesis in Cx43-expressing cells required heterocellular GJIC. Further study revealed that the gastric cancer cells transmigrated through the intercellular space between the mesothelial cells via a paracellular route. Our results suggest that the abnormal expression of Cx43 plays an essential role in peritoneal metastasis and that Cx43-mediated heterocellular GJIC between gastric cancer cells and mesothelial cells may be an important regulatory step during metastasis. Finally, we observed that the diapedesis of exfoliated gastric cancer cells through mesothelial barriers is a viable route of paracellular migration.
PMCID: PMC3770585  PMID: 24040271
24.  The Construction and Expression of Lysine-Rich Gene in the Mammary Gland of Transgenic Mice 
DNA and Cell Biology  2012;31(8):1372-1383.
Lysine is the limiting amino acid in cereal grains, which represent a major source of human food and animal feed worldwide, and is considered the most important of the essential amino acids. In this study, β-casein, αS2-casein, and lactotransferrin cDNA clone fragments encoding lysine-rich peptides were fused together to generate a lysine-rich (LR) gene and the mammary gland-specific expression vector pBC1-LR-NEOr was constructed. Transgenic mice were generated by pronuclear microinjection of the linearized expression vectors harboring the LR transgene. The transgenic mice and their offspring were examined using multiplex polymerase chain reaction (PCR), Southern blotting, reverse transcriptase–PCR, in situ hybridization, and Western blotting techniques. Our results showed that the LR gene was successfully integrated into the mouse genome and was transmitted stably. The specific LR gene expression was restricted to the mammary gland, active alveoli of the transgenic female mice during lactation. The lysine level of the two transgenic lines was significantly higher than that of nontransgenic controls (p<0.05). In addition, the growth performance of transgenic pups was enhanced by directly feeding them the LR protein-enriched transgenic milk. Our results demonstrated that lysine-rich gene was successfully constructed and expressed in mammary gland of transgenic mice. This study will provide a better understanding of how mammary gland expression systems that increase the lysine content of milk can be applied to other mammals, such as cows.
They demonstrate the successful production of a transgenic mouse expressing a lysine-rich gene in milk and suggest its potential application for drug development.
PMCID: PMC3405455  PMID: 22577831
25.  Proliferative Capacity and Pluripotent Characteristics of Porcine Adult Stem Cells Derived from Adipose Tissue and Bone Marrow 
Cellular Reprogramming  2012;14(4):342-352.
Direct reprogramming of somatic cells to induced pluripotent stem cells (iPSCs) provides an invaluable resource for regenerative medicine. Because of some ethical and logistical barriers, human iPSCs cannot be used to generate a chimera, which is one of markers representing pluripotency. As the most attractive model for preclinical studies, pigs offer another path to improve clinical medicine. In this study, porcine adult stem cells (pASCs), including adipose mesenchymal stem cells (AMSCs) and bone marrow mesenchymal stem cells (BMSCs), were collected and cultured under the same conditions in vitro. Real-time PCR, immunocytochemical staining, apoptosis analysis, and induced differentiation and reprogramming techniques were used to investigate the proliferative capacity and pluripotent characteristics of pASCs. Our results showed that both AMSCs and BMSCs displayed a similar immunophenotype, and their proliferative capacity appeared as a downward trend as the cell passage number increased. The cell proliferative capacity of AMSCs was significantly lower than that of BMSCs (p<0.05). Moreover, each type of pASCs went through 20 passages without undergoing alterations in the expression of reprogramming transcriptional factors (Oct4, Sox2, c-Myc, and Nanog). All pASCs had adipogenic and osteogenic differentiation potential. In addition, they also could be reprogrammed to pig induced pluripotent stem cells (piPSCs) with similar time and efficiency. In conclusion, porcine BMSCs had a higher proliferative capacity than AMSCs, and the pluripotency of pASCs was stable in long-term culture.
PMCID: PMC3411367  PMID: 22775457

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