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1.  15NH4+ excretion test: a new method for detection of Helicobacter pylori infection. 
Journal of Clinical Microbiology  1992;30(1):181-184.
A noninvasive test for the detection of Helicobacter pylori infection that uses [15N]urea as a tracer has been established. The principle the test is based on is the strong urease activity of H. pylori. After oral ingestion, [15N]urea is broken down into ammonia and carbon dioxide by H. pylori urease in the stomach. The ammonia is absorbed into the blood and excreted in the urine. The amount of [15N]urea, reflecting the magnitude of H. pylori infection, is evaluated by measuring the abundance and excretion rate of 15N in ammonia in the urine. Thirty-six patients were examined in our study. The 15N excretion rates in urine ammonia of patients who were H. pylori positive were significantly higher than those of H. pylori-negative patients (P less than 0.05). Twenty-three patients were H. pylori positive by Gram stain and culture. The sensitivity of the 15NH4 excretion test compared with these techniques was 96%, and no false positives were obtained. The 15NH4+ excretion rates of 13 H. pylori-negative subjects were all in the normal range (less than 0.3%). This method is a simple, precise, highly sensitive, noninvasive, nonradioactive test. It could be used for diagnosis as well as for the followup of patients receiving H. pylori eradication therapy, especially children and pregnant women. It could also be used in epidemiological investigation of H. pylori infection in a general population.
PMCID: PMC265017  PMID: 1734051
2.  Gender differences in pulmonary regenerative response to naphthalene-induced bronchiolar epithelial cell injury 
Cell proliferation  2009;42(5):672-687.
Accumulating evidence suggests that gender affects the incidence and severity of several pulmonary diseases. Previous studies on mice have shown gender differences in susceptibility to naphthalene-induced lung injury, where Clara cell damage was found to occur earlier and to be more extensive in females than in males. However, very little is known about whether there are any gender differences in subsequent lung repair responses. The aim of this study was to investigate whether gender plays an important role in pulmonary regenerative response to naphthalene-induced Clara cell ablation.
Materials and methods
Adult male and female mice were injected with a low, medium, or high dose of naphthalene, and lung tissue regeneration was examined by immunohistochemical staining for cell proliferation marker (Ki-67) and mitosis marker (phosphohistone-3).
Histopathological analysis showed that naphthalene-induced Clara cell necrosis was more prominent in the lungs of female mice as compared to male mice. Cell proliferation and mitosis in both the distal bronchiolar airway epithelium and peribronchiolar interstitium of female mice was significantly greater than that of male mice after treatment with the low and medium doses. However, after treatment with high dose of naphthalene, lung regeneration was delayed in female mice, while male mice mounted a timely regenerative response.
These findings show that there are clear gender differences in naphthalene-induced lung injury and repair.
PMCID: PMC4514530  PMID: 19614675 CAMSID: cams271
3.  PU.1 is essential for MLL leukemia partially via crosstalk with the MEIS/HOX pathway 
Zhou, J | Wu, J | Li, B | Liu, D | Yu, J | Yan, X | Zheng, S | Wang, J | Zhang, L | Zhang, L | He, F | Li, Q | Chen, A | Zhang, Y | Zhao, X | Guan, Y | Zhao, X | Yan, J | Ni, J | Nobrega, MA | Löwenberg, B | Delwel, R | Valk, PJM | Kumar, A | Xie, L | Tenen, DG | Huang, G | Wang, Q-f
Leukemia  2013;28(7):1436-1448.
Mixed lineage leukemia (MLL) fusion proteins directly activate the expression of key downstream genes such as MEIS1, HOXA9 to drive an aggressive form of human leukemia. However, it is still poorly understood what additional transcriptional regulators, independent of the MLL fusion pathway, contribute to the development of MLL leukemia. Here we show that the transcription factor PU.1 is essential for MLL leukemia and is required for the growth of MLL leukemic cells via the promotion of cell-cycle progression and inhibition of apoptosis. Importantly, PU.1 expression is not under the control of MLL fusion proteins. We further identified a PU.1-governed 15-gene signature, which contains key regulators in the MEIS-HOX program (MEIS1, PBX3, FLT3, and c-KIT). PU.1 directly binds to the genomic loci of its target genes in vivo, and is required to maintain active expression of those genes in both normal hematopoietic stem and progenitor cells and in MLL leukemia. Finally, the clinical significance of the identified PU.1 signature was indicated by its ability to predict survival in acute myelogenous leukemia patients. Together, our findings demonstrate that PU.1 contributes to the development of MLL leukemia, partially via crosstalk with the MEIS/HOX pathway.
PMCID: PMC4410691  PMID: 24445817
PU.1; MEIS1; MLL leukemia; transcription regulation
4.  Gigantism and Acromegaly Due to Xq26 Microduplications and GPR101 Mutation 
The New England journal of medicine  2014;371(25):2363-2374.
Increased secretion of growth hormone leads to gigantism in children and acromegaly in adults; the genetic causes of gigantism and acromegaly are poorly understood.
We performed clinical and genetic studies of samples obtained from 43 patients with gigantism and then sequenced an implicated gene in samples from 248 patients with acromegaly.
We observed microduplication on chromosome Xq26.3 in samples from 13 patients with gigantism; of these samples, 4 were obtained from members of two unrelated kindreds, and 9 were from patients with sporadic cases. All the patients had disease onset during early childhood. Of the patients with gigantism who did not carry an Xq26.3 microduplication, none presented before the age of 5 years. Genomic characterization of the Xq26.3 region suggests that the microduplications are generated during chromosome replication and that they contain four protein-coding genes. Only one of these genes, GPR101, which encodes a G-protein–coupled receptor, was overexpressed in patients’ pituitary lesions. We identified a recurrent GPR101 mutation (p.E308D) in 11 of 248 patients with acromegaly, with the mutation found mostly in tumors. When the mutation was transfected into rat GH3 cells, it led to increased release of growth hormone and proliferation of growth hormone–producing cells.
We describe a pediatric disorder (which we have termed X-linked acrogigantism [X-LAG]) that is caused by an Xq26.3 genomic duplication and is characterized by early-onset gigantism resulting from an excess of growth hormone. Duplication of GPR101 probably causes X-LAG. We also found a recurrent mutation in GPR101 in some adults with acromegaly. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and others.)
PMCID: PMC4291174  PMID: 25470569
5.  Differential expression and adherence of Porphyromonas gingivalis FimA genotypes 
Molecular oral microbiology  2011;26(6):388-395.
Porphyromonas gingivalis is a primary pathogen involved in the initiation and progression of adult chronic periodontitis. Its colonization on oral surfaces is a necessary first step leading to infection. FimA, a subunit protein of major (long) fimbriae, is a well-known virulence factor. Based on its nucleotide sequence, FimA is classified into several genotypes. We compared here the transcriptional levels of the fimA gene in several P. gingivalis strains using real-time polymerase chain reaction analysis, fimbrial display on the P. gingivalis surface using transmission electronic microscopy, and the adherence competencies of P. gingivalis strains carrying different types of FimAs towards saliva and Streptococcus gordonii surfaces using mutagenesis analysis. We demonstrated differential expression of each fimA gene in these P. gingivalis strains. A correlation of the transcription level of fimA and binding activity of P. gingivalis was revealed. We show that P. gingivalis strains with genotype I and II of FimA are efficient in interaction with saliva or S. gordonii. This work highlights the important role of FimA type I and II in P. gingivalis attachment to oral surfaces.
PMCID: PMC4451598  PMID: 22053966
colonization; fimbriae; gene expression; gene knockouts
6.  Endothelial cell specific adhesion molecule (ESAM) localizes to platelet–platelet contacts and regulates thrombus formation in vivo 
In resting platelets, endothelial cell specific adhesion molecule (ESAM) is located in alpha granules, increasing its cell surface expression following platelet activation. However, the function of ESAM on platelets is unknown.
To determine whether ESAM has a role in thrombus formation.
Methods and results
We found that following platelet activation ESAM localizes to the junctions between adjacent platelets, suggesting a role for this protein in contact-dependent events that regulate thrombus formation. To test this hypothesis we examined the effect of ESAM deletion on platelet function. In vivo, ESAM−/− mice achieved more stable hemostasis than wild-type mice following tail transection, and developed larger thrombi following laser injury of cremaster muscle arterioles. In vitro, ESAM−/− platelets aggregated at lower concentrations of G protein-dependent agonists than wild-type platelets, and were more resistant to disaggregation. In contrast, agonist-induced calcium mobilization, αIIbβ3 activation, alpha-granule secretion and platelet spreading, were normal in ESAM-deficient platelets. To understand the molecular mechanism by which ESAM regulates platelet activity, we utilized a PDZ domain array to identify the scaffold protein NHERF-1 as an ESAM binding protein, and further demonstrated that it associates with ESAM in both resting and activated platelets.
These findings support a model in which ESAM localizes to platelet contacts following platelet activation in order to limit thrombus growth and stability so that the optimal hemostatic response occurs following vascular injury.
PMCID: PMC4441405  PMID: 19740102
ESAM; NHERF-1; PDZ domain; platelets; thrombosis
7.  Antioxidant and Hypoglycemic Activities of Exopolysaccharide by Submerged Culture of Inocutus Hispidus 
This work was to investigate the hypoglycemic and antioxidant activities of the exopolysaccharides produced in a stirred-tank bioreactor by Inocutus hispidus. The exopolysaccharides showed significant antioxidant activities, up to 70.7±2.5% inhibition of hydroxyl radicals, 50% inhibition of 2,2-diphenyl-1-picrylhydrazyl radicals, and a Trolox equivalent antioxidant capacity of 3.3 mM. The exopolysaccharide also showed notable hypoglycemic effects in streptozotocin-induced diabetic mice, reducing the plasma glucose, total cholesterol and triacylglycerol concentrations by 18.2±1.5, 20.9±0.8 and 14.4±0.4, respectively. The results demonstrated the potential of this EPS for human health protection against oxidative damage and hyperglycemia.
PMCID: PMC4502154  PMID: 26180285
Exopolysaccharides; Inocutus hispidus; fermentation; hypoglycemic effect; antioxidant
8.  A novel staging model to classify oesophageal squamous cell carcinoma patients in China 
Tan, H | Zhang, H | Xie, J | Chen, B | Wen, C | Guo, X | Zhao, Q | Wu, Z | Shen, J | Wu, J | Xu, X | Li, E | Xu, L | Wang, X
British Journal of Cancer  2014;110(8):2109-2115.
Oesophageal squamous cell carcinoma (ESCC) is the predominant subtype of oesophageal carcinoma in China, with the overall 5-year survival rate of <10%. The current tumour-node-metastasis (TNM) staging system has become so complex that it is not easy to use in the life expectancy assessment. We aim to combine clinical variables and biomarkers to develop and validate a relative simple and reliable model, named the FENSAM, for ESCC prognosis.
To build the FENSAM, we analysed 22 potential prognostic factors from 461 patients, including 9 biomarkers (Ezrin, Fascin, desmocollin 2 (DSC2), pFascin, activating transcription factor 3 (ATF3), connective-tissue growth factor (CTGF), neutrophil gelatinase-associated lipocalin (NGAL), NGAL receptor (NGALR), and cysteine-rich angiogenic protein 61 (CYR61)) and other 13 clinical variables. We selected significant factors associated with survival of ESCC patients, and used them to build our FENSAM model. We then obtained the hazard risk score of the model to classify ESCC patients. In addition, we validated the model in an independent cohort of 290 patients from the same hospital. The predictive performance of the model was assessed by the Area under the Receiver Operating Characteristic Curve (AUC) and Kaplan–Meier survival analysis.
We found six markers significantly associated with survival of ESCC patients (Ezrin, Fascin, ATF3, surgery extent, N-stage, and M-stage). They were combined to create a novel four-stage FENSAM model for patients' classification. FENSAM possessed a high classification precision similar to the TNM staging system, but with a much simpler model. The efficiency of FENSAM was evaluated by different quantiles of AUC and the results of survival analysis. The validation result demonstrated the potential of the FENSAM model to improve classification accuracy for ESCC patients
FENSAM provides an alternative classifier for ESCC patients with a high classification precision using a simple model.
PMCID: PMC3992487  PMID: 24569468
FENSAM; TNM stage system; biomarker; ESCC; LASSO
9.  Associations of the major international high-risk resistant clones and virulent clones with specific ompK36 allele groups in Klebsiella pneumoniae in Taiwan 
This study was conducted to investigate the association between ompK36 variants and international high-risk clones in Klebsiella pneumoniae. Fifty-nine sequence types (STs) divided into four ompK36 allele groups (groups A to D) were identified among 185 K. pneumoniae isolates. The major high-risk clones (29 ST11, 13 ST15, 7 ST37 and 1 ST147 isolates) were assigned to group A, while 6 STs (15 ST23, 2 ST65, 3 ST86, 1 ST163, 1 ST373 and 2 ST375 isolates) associated with pyogenic liver abscess were assigned to group C. The genotyping assay developed in this study may be useful for screening of epidemic STs.
PMCID: PMC4366441  PMID: 25834737
High-risk clones; Klebsiella pneumoniae; multilocus sequence typing; pyogenic liver abscess; sequence types
10.  Symptoms of endocrine treatment and outcome in the BIG 1–98 study 
There may be a relationship between the incidence of vasomotor and arthralgia/myalgia symptoms and treatment outcomes for postmenopausal breast cancer patients with endocrine-responsive disease who received adjuvant letrozole or tamoxifen.
Patients and methods
Data on patients randomized into the monotherapy arms of the BIG 1–98 clinical trial who did not have either vasomotor or arthralgia/myalgia/carpal tunnel (AMC) symptoms reported at baseline, started protocol treatment and were alive and disease-free at the 3-month landmark (n=4798) and at the 12-month landmark (n=4682) were used for this report. Cohorts of patients with vasomotor symptoms, AMC symptoms, neither, or both were defined at both 3 and 12 months from randomization. Landmark analyses were performed using Kaplan-Meier method for disease-free survival (DFS) and competing risk methodology for breast cancer free interval (BCFI). Median follow-up was 7.0 years.
Reporting of AMC symptoms was associated with better outcome for both the 3- and 12-month landmark analyses (e.g. 12-month landmark, HR (95% CI) for DFS=0.65 (0.49–0.87), and for BCFI=0.70 (0.49–0.99)). By contrast, reporting of vasomotor symptoms was less clearly associated with DFS (12-month DFS HR (95% CI)=0.82 (0.70–0.96)) and BCFI (12-month DFS HR (95% CI)=0.97 (0.80–1.18). Interaction tests indicated no effect of treatment group on associations between symptoms and outcomes.
While reporting of AMC symptoms was clearly associated with better DFS and BCFI, the association between vasomotor symptoms and outcome was less clear, especially with respect to breast cancer-related events.
PMCID: PMC3913479  PMID: 24305979
aromatase inhibitor; side effects; breast cancer; endocrine therapy
11.  Targeting focal adhesion turnover in invasive breast cancer cells by the purine derivative reversine 
British Journal of Cancer  2013;109(11):2810-2818.
The dynamics of focal adhesion (FA) turnover is a key determinant for the regulation of cancer cell migration. Here we investigated FA turnover in a panel of breast cancer models with distinct invasive properties and evaluated the impact of reversine on this turnover in relation to cancer cell invasion in in vitro and in vivo conditions.
Live imaging and immunofluorescence assays were used to investigate FA turnover in breast cancer cells. Biochemical studies were used to investigate the impact of reversine on FA signalling and turnover. In vivo activity was investigated using orthotopic breast cancer mouse models.
Accelerated FA disassembly from plasma membrane protrusions was observed in invasive compared with non-invasive breast cancer cells or non-immortalised mammary epithelial cells. Reversine significantly inhibited FA disassembly leading to stable FAs, which was associated with reduced cell motility and invasion. The inhibitory effect of reversine on FA turnover accounted for a large part on its capacity to interfere with FAK function on regulating its downstream targets. In orthotopic breast cancer mouse models, reversine revealed a potent inhibitory activity on tumour progression to metastasis.
These results support the utility of targeting FA turnover as a therapeutic approach for invasive breast cancer.
PMCID: PMC3844920  PMID: 24169345
focal adhesion turnover; cell invasion; metastasis; reversine
12.  The relationship of respiratory and cardiovascular hospital admissions to the southern California wildfires of 2003 
There is limited information on the public health impact of wildfires. The relationship of cardiorespiratory hospital admissions (n = 40 856) to wildfire-related particulate matter (PM2.5) during catastrophic wildfires in southern California in October 2003 was evaluated.
Zip code level PM2.5 concentrations were estimated using spatial interpolations from measured PM2.5, light extinction, meteorological conditions, and smoke information from MODIS satellite images at 250 m resolution. Generalised estimating equations for Poisson data were used to assess the relationship between daily admissions and PM2.5, adjusted for weather, fungal spores (associated with asthma), weekend, zip code-level population and sociodemographics.
Associations of 2-day average PM2.5 with respiratory admissions were stronger during than before or after the fires. Average increases of 70 μg/m3 PM2.5 during heavy smoke conditions compared with PM2.5 in the pre-wildfire period were associated with 34% increases in asthma admissions. The strongest wildfire-related PM2.5 associations were for people ages 65– 99 years (10.1% increase per 10 μg/m3 PM2.5, 95% CI 3.0% to 17.8%) and ages 0–4 years (8.3%, 95% CI 2.2% to 14.9%) followed by ages 20–64 years (4.1%, 95% CI 20.5% to 9.0%). There were no PM2.5–asthma associations in children ages 5–18 years, although their admission rates significantly increased after the fires. Per 10 μg/m3 wildfire-related PM2.5, acute bronchitis admissions across all ages increased by 9.6% (95% CI 1.8% to 17.9%), chronic obstructive pulmonary disease admissions for ages 20–64 years by 6.9% (95% CI 0.9% to 13.1%), and pneumonia admissions for ages 5–18 years by 6.4% (95% CI 21.0% to 14.2%). Acute bronchitis and pneumonia admissions also increased after the fires. There was limited evidence of a small impact of wildfire-related PM2.5 on cardiovascular admissions.
Wildfire-related PM2.5 led to increased respiratory hospital admissions, especially asthma, suggesting that better preventive measures are required to reduce morbidity among vulnerable populations.
PMCID: PMC4176821  PMID: 19017694
13.  Distribution of TMEM100 in the mouse and human gastrointestinal tract - a novel marker of enteric nerves 
Neuroscience  2013;240:117-128.
Identification of markers of enteric neurons has contributed substantially to our understanding of the development, normal physiology, and pathology of the gut. Previously identified markers of the enteric nervous system can be used to label all or most neuronal structures or for examining individual cells by labeling just the nucleus or cell body. Most of these markers are excellent but have some limitations. TMEM100 is a gene at locus 17q32 encoding a 134-amino acid protein with two hypothetical transmembrane domains. TMEM100 expression has not been reported in adult mammalian tissues but does appear in the ventral neural tube of embryonic mice and plays a role in signaling pathways associated with development of the enteric nervous system. We showed that TMEM100 messenger RNA is expressed in the gastrointestinal tract and demonstrated that TMEM100 is a membrane associated protein. Furthermore TMEM100 immunoreactivity was restricted to enteric neurons and vascular tissue in the muscularis propria of all regions of the mouse and human gastrointestinal tract. TMEM100 immunoreactivity co-localized with labeling for the pan-neuronal marker protein gene product 9.5 (PGP9.5) but not with the glial marker S100β or Kit, a marker of interstitial cells of Cajal. The signaling molecule, bone morphogenetic protein (BMP) 4, was also expressed in enteric neurons of the human colon and colocalized with TMEM100. TMEM100 is also expressed in neuronal cell bodies and fibers in the mouse brain and dorsal root ganglia. We conclude that TMEM100 is a novel, membrane-associated marker for enteric nerves and is as effective as PGP9.5 for identifying neuronal structures in the gastrointestinal tract. The expression of TMEM100 in the enteric nervous system may reflect a role in the development and differentiation of cells through a transforming growth factor β, BMP or related signaling pathway.
PMCID: PMC3637859  PMID: 23485812
TMEM100; enteric nervous system; PGP9.5; TGFβ signaling; BMP4
14.  High-Precision Distribution of Highly Stable Optical Pulse Trains with 8.8 × 10−19 instability 
Scientific Reports  2014;4:5109.
The high-precision distribution of optical pulse trains via fibre links has had a considerable impact in many fields. In most published work, the accuracy is still fundamentally limited by unavoidable noise sources, such as thermal and shot noise from conventional photodiodes and thermal noise from mixers. Here, we demonstrate a new high-precision timing distribution system that uses a highly precise phase detector to obviously reduce the effect of these limitations. Instead of using photodiodes and microwave mixers, we use several fibre Sagnac-loop-based optical-microwave phase detectors (OM-PDs) to achieve optical-electrical conversion and phase measurements, thereby suppressing the sources of noise and achieving ultra-high accuracy. The results of a distribution experiment using a 10-km fibre link indicate that our system exhibits a residual instability of 2.0 × 10−15 at1 s and8.8 × 10−19 at 40,000 s and an integrated timing jitter as low as 3.8 fs in a bandwidth of 1 Hz to 100 kHz. This low instability and timing jitter make it possible for our system to be used in the distribution of optical-clock signals or in applications that require extremely accurate frequency/time synchronisation.
PMCID: PMC4037707  PMID: 24870442
15.  Lentiviral-mediated RNAi targeting caspase-3 inhibits apoptosis induced by serum deprivation in rat endplate chondrocytes in vitro  
Current studies find that degenerated cartilage endplates (CEP) of vertebrae, with fewer diffusion areas, decrease nutrient supply and accelerate intervertebral disc degeneration. Many more apoptotic cells have been identified in degenerated than in normal endplates, and may be responsible for the degenerated grade. Previous findings suggest that inhibition of apoptosis is one possible approach to improve disc regeneration. It is postulated that inhibition of CEP cell apoptosis may be responsible for the regeneration of endplates. Caspase-3, involved in the execution phase of apoptosis, is a candidate for regulating the apoptotic process. In the present study, CEP cells were incubated in 1% fetal bovine serum. Activated caspases were detected to identify the apoptotic pathway, and apoptosis was quantified by flow cytometry. Lentiviral caspase-3 short hairpin RNA (shRNA) was employed to study its protective effects against serum deprivation. Silencing of caspase-3 expression was quantified by reverse transcription-polymerase chain reaction and Western blots, and inhibition of apoptosis was quantified by flow cytometry. Serum deprivation increased apoptosis of rat CEP cells through activation of a caspase cascade. Lentiviral caspase-3 shRNA was successfully transduced into CEP cells, and specifically silenced endogenous caspase-3 expression. Surviving cells were protected by the downregulation of caspase-3 expression and activation. Thus, lentiviral caspase-3 shRNA-mediated RNAi successfully silenced endogenous caspase-3 expression, preventing inappropriate or premature apoptosis.
PMCID: PMC4086170  PMID: 24878605
Cartilaginous endplate; Chondrocytes; RNA interference; Apoptosis; Caspase-3; Serum deprivation
16.  Imaging and elemental mapping of biological specimens with a dual-EDS dedicated scanning transmission electron microscope 
Ultramicroscopy  2013;128:24-31.
A dedicated analytical scanning transmission electron microscope (STEM) with dual energy dispersive spectroscopy (EDS) detectors has been designed for complementary high performance imaging as well as high sensitivity elemental analysis and mapping of biological structures. The performance of this new design, based on a Hitachi HD-2300A model, was evaluated using a variety of biological specimens. With three imaging detectors, both the surface and internal structure of cells can be examined simultaneously. The whole-cell elemental mapping, especially of heavier metal species that have low cross-section for electron energy loss spectroscopy (EELS), can be faithfully obtained. Optimization of STEM imaging conditions is applied to thick sections as well as thin sections of biological cells under low-dose conditions at room- and cryogenic temperatures. Such multimodal capabilities applied to soft/biological structures usher a new era for analytical studies in biological systems.
PMCID: PMC3658130  PMID: 23500508
17.  Spatiotemporal path discontinuities of wavepackets propagating across a meta-atom 
Scientific Reports  2014;4:4634.
The realization of phase discontinuities across metasurfaces has led to a new class of reflection and refraction. Here we present theory and experiment on the discontinuous propagation of wavepackets across subwavelength-thickness meta-atoms. Using acoustic waves, we observe the process of wavepackets traversing a meta-atom with abrupt displacements, which appear as path discontinuities on a space-time diagram. We construct a tunable meta-atom from two coupled resonators at ~500 Hz, map the spatiotemporal trajectories of individual sonic pulses, and reveal discontinuities at the meta-atom where the pulses exit at a time ~50 ms ahead or behind their arrivals. Applications include thin acoustic metasurface lenses.
PMCID: PMC3985075  PMID: 24728015
19.  Activation of Sonic hedgehog signaling in neural progenitor cells promotes glioma development in the zebrafish optic pathway 
Oncogenesis  2014;3(3):e96-.
Dysregulation of Sonic hedgehog (Shh) signaling has been implicated in glioma pathogenesis. Yet, the role of this pathway in gliomagenesis remains controversial because of the lack of relevant animal models. Using the cytokeratin 5 promoter, we ectopically expressed a constitutively active zebrafish Smoothened (Smoa1) in neural progenitor cells and analyzed tumorigenic capacity of activated Shh signaling in both transient and stable transgenic fish. Transient transgenic fish overexpressing Smoa1 developed retinal and brain tumors, suggesting smoa1 is oncogenic in the zebrafish central nervous system (CNS). We further established stable transgenic lines that simultaneously developed optic pathway glioma (OPG) and various retinal tumors. In one of these lines, up to 80% of F1 and F2 fish developed tumors within 1 year of age. Microarray analysis of tumor samples showed upregulated expression of genes involved in the cell cycle, cancer signaling and Shh downstream targets ptc1, gli1 and gli2a. Tumors also exhibited specific gene signatures characteristic of radial glia and progenitor cells as transcriptions of radial glia genes cyp19a1b, s100β, blbp, gfap and the stem/progenitor genes nestin and sox2 were significantly upregulated. Overexpression of GFAP, S100β, BLBP and Sox2 was confirmed by immunofluorescence. We also detected overexpression of Mdm2 throughout the optic pathway in fish with OPG, therefore implicating the Mdm2–Tp53 pathway in glioma pathogenesis. In conclusion, we demonstrate that activated Shh signaling initiates tumorigenesis in the zebrafish CNS and provide the first OPG model not associated with neurofibromatosis 1.
PMCID: PMC4038393  PMID: 24686726
zebrafish; Sonic hedgehog (Shh) pathway; activated Smoothened (Smoa1); optic pathway glioma (OPG)
20.  Microstructural percolation assisted breakthrough of trade-off between strength and ductility in CuZr-based metallic glass composites 
Scientific Reports  2014;4:4167.
As two important mechanical properties, strength and ductility generally tend to be muturally exclusive in conventional engineering materials. The breakthrough of such a trade-off has been potentiated by the recently developed CuZr-based bulk metallic glass (BMG) composites ductilized by a shape memory CuZr(B2) phase. Here the microstructural dependences of tensile properties for the CuZr-based BMG composites were elucidated qualitatively and modeled quantitatively, and the underlying mechanisms were unraveled. Through the microstructural percolation induced by matching the length scales of particle size and interparticle spacing, a notable breakthrough was achieved in the composites that the general conflicts between strength and ductility can be defeated. This study is expected to greatly aid in the microstructural design and tailoring for improved properties of BMG composites. It also has implications for the development of strong and ductile materials in the future.
PMCID: PMC3933912  PMID: 24566737
21.  Suppression of tumor angiogenesis by targeting the protein neddylation pathway 
Cell Death & Disease  2014;5(2):e1059-.
Inhibition of protein neddylation, particularly cullin neddylation, has emerged as a promising anticancer strategy, as evidenced by the antitumor activity in preclinical studies of the Nedd8-activating enzyme (NAE) inhibitor MLN4924. This small molecule can block the protein neddylation pathway and is now in clinical trials. We and others have previously shown that the antitumor activity of MLN4924 is mediated by its ability to induce apoptosis, autophagy and senescence in a cell context-dependent manner. However, whether MLN4924 has any effect on tumor angiogenesis remains unexplored. Here we report that MLN4924 inhibits angiogenesis in various in vitro and in vivo models, leading to the suppression of tumor growth and metastasis in highly malignant pancreatic cancer, indicating that blockage of angiogenesis is yet another mechanism contributing to its antitumor activity. At the molecular level, MLN4924 inhibits Cullin–RING E3 ligases (CRLs) by cullin deneddylation, causing accumulation of RhoA at an early stage to impair angiogenic activity of vascular endothelial cells and subsequently DNA damage response, cell cycle arrest and apoptosis due to accumulation of other tumor-suppressive substrates of CRLs. Furthermore, we showed that inactivation of CRLs, via small interfering RNA (siRNA) silencing of its essential subunit ROC1/RBX1, recapitulates the antiangiogenic effect of MLN4924. Taken together, our study demonstrates a previously unrecognized role of neddylation in the regulation of tumor angiogenesis using both pharmaceutical and genetic approaches, and provides proof of concept evidence for future development of neddylation inhibitors (such as MLN4924) as a novel class of antiangiogenic agents.
PMCID: PMC3944239  PMID: 24525735
neddylation; MLN4924; tumor angiogenesis; cullin–RING ligase
22.  Identification of serum CCL15 in hepatocellular carcinoma 
Li, Y | Wu, J | Zhang, W | Zhang, N | Guo, H
British Journal of Cancer  2013;108(1):99-106.
Early serum detection is of critical importance to improve the therapy for hepatocellular carcinoma (HCC), one of the most deadly cancers. Hepatitis infection is a leading cause of HCC.
In the present study, we collected total serum samples with informed consent from 80 HCC patients with HBV (+)/cirrhosis (+), 80 patients with benign diseases (50 liver cirrhosis patients and 30 HBV-infected patients) and 60 healthy controls. Analysis was by using surface-enhanced laser desorption/ionisation-time-of-flight mass spectroscopy (SELDI-TOF-MS) to find new serum markers of HCC. SELDI peaks were isolated by SDS–PAGE, identified by LC-MS/MS and validated by immunohistochemistry (IHC) in liver tissues. Migration and invasion assay were performed to test the ability of cell migration and invasion in vitro.
SELDI-TOF-MS revealed a band at 7777 M/Z in the serum samples from HCC patients but not from healthy controls or patients with benign diseases. The protein (7777.27 M/Z) in the proteomic signature was identified as C-C motif chemokine 15 (CCL15) by peptide mass fingerprinting. A significant increase in serum CCL15 was detected in HCC patients. Functional analysis showed that HCC cell expressed CCL15, which in turn promoted HCC cell migration and invasion.
CCL15 may be a specific proteomic biomarker of HCC, which has an important role in tumorigenesis and tumour invasion.
PMCID: PMC3553511  PMID: 23321514
CCL15; biomarker; HCC; migration; invasion
23.  Magnetic and structural transitions of SrFe2As2 at high pressure and low temperature 
Scientific Reports  2014;4:3685.
One of key issues in studying iron based superconductors is to understand how the magnetic phase of the parent compounds evolves. Here we report the systematic investigation of paramagnetic to antiferromagnetic and tetragonal to orthorhombic structural transitions of “122” SrFe2As2 parent compound using combined high resolution synchrotron Mössbauer spectroscopy and x-ray diffraction techniques in a cryogenically cooled high pressure diamond anvil cell. It is found that although the two transitions are coupled at 205 K at ambient pressure, they are concurrently suppressed to much lower temperatures near a quantum critical pressure of approximately 4.8 GPa where the antiferromagnetic state transforms into bulk superconducting state. Our results indicate that the lattice distortions and magnetism jointly play a critical role in inducing superconductivity in iron based compounds.
PMCID: PMC3890939  PMID: 24418845
24.  Identification and functional analysis of 9p24 amplified genes in human breast cancer 
Oncogene  2011;31(3):10.1038/onc.2011.227.
Previously, our group identified a novel amplicon at chromosome 9p24 in human esophageal and breast cancers, and cloned the novel gene, GASC1 (gene amplified in squamous cell carcinoma 1, also known as JMJD2C/KDM4C), from this amplicon. GASC1 is a histone demethylase involved in the deregulation of histone methylation in cancer cells. In the current study, we aimed to comprehensively characterize the genes in the 9p24 amplicon in human breast cancer. We performed extensive genomic analyses on a panel of cancer cell lines and narrowed the shortest region of overlap to approximately 2 Mb. Based on statistical analysis of copy number increase and overexpression, the 9p24 amplicon contains six candidate oncogenes. Among these, four genes (GASC1 UHRF2, KIAA1432 and C9orf123) are overexpressed only in the context of gene amplification while two genes (ERMP1 and IL33) are overexpressed independent of the copy number increase. We then focused our studies on the UHRF2 gene, which has a potential involvement in both DNA methylation and histone modification. Knocking down UHRF2 expression inhibited the growth of breast cancer cells specifically with 9p24 amplification. Conversely, ectopic overexpression of UHRF2 in non-tumorigenic MCF10A cells promoted cell proliferation. Furthermore, we demonstrated that UHRF2 has the ability to suppress the expression of key cell-cycle inhibitors, such as p16INK4a, p21Waf1/Cip1 and p27Kip1. Taken together, our studies support the notion that the 9p24 amplicon contains multiple oncogenes that may integrate genetic and epigenetic codes and have important roles in human tumorigenesis.
PMCID: PMC3886828  PMID: 21666724
chromosome 9p24; GASC1; UHRF2; gene amplification
25.  Dynamics of ASXL1 mutation and other associated genetic alterations during disease progression in patients with primary myelodysplastic syndrome 
Blood Cancer Journal  2014;4(1):e177-.
Recently, mutations of the additional sex comb-like 1 (ASXL1) gene were identified in patients with myelodysplastic syndrome (MDS), but the interaction of this mutation with other genetic alterations and its dynamic changes during disease progression remain to be determined. In this study, ASXL1 mutations were identified in 106 (22.7%) of the 466 patients with primary MDS based on the French-American-British (FAB) classification and 62 (17.1%) of the 362 patients based on the World Health Organization (WHO) classification. ASXL1 mutation was closely associated with trisomy 8 and mutations of RUNX1, EZH2, IDH, NRAS, JAK2, SETBP1 and SRSF2, but was negatively associated with SF3B1 mutation. Most ASXL1-mutated patients (85%) had concurrent other gene mutations at diagnosis. ASXL1 mutation was an independent poor prognostic factor for survival. Sequential studies showed that the original ASXL1 mutation remained unchanged at disease progression in all 32 ASXL1-mutated patients but were frequently accompanied with acquisition of mutations of other genes, including RUNX1, NRAS, KRAS, SF3B1, SETBP1 and chromosomal evolution. On the other side, among the 80 ASXL1-wild patients, only one acquired ASXL1 mutation at leukemia transformation. In conclusion, ASXL1 mutations in association with other genetic alterations may have a role in the development of MDS but contribute little to disease progression.
PMCID: PMC3913943  PMID: 24442206
ASXL1 mutation; myelodysplastic syndrome; sequential analyses; prognosis

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