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1.  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
2.  TBX6 Null Variants and a Common Hypomorphic Allele in Congenital Scoliosis 
The New England journal of medicine  2015;372(4):341-350.
Congenital scoliosis is a common type of vertebral malformation. Genetic susceptibility has been implicated in congenital scoliosis.
We evaluated 161 Han Chinese persons with sporadic congenital scoliosis, 166 Han Chinese controls, and 2 pedigrees, family members of which had a 16p11.2 deletion, using comparative genomic hybridization, quantitative polymerase-chain-reaction analysis, and DNA sequencing. We carried out tests of replication using an additional series of 76 Han Chinese persons with congenital scoliosis and a multi-center series of 42 persons with 16p11.2 deletions.
We identified a total of 17 heterozygous TBX6 null mutations in the 161 persons with sporadic congenital scoliosis (11%); we did not observe any null mutations in TBX6 in 166 controls (P<3.8×10−6). These null alleles include copy-number variants (12 instances of a 16p11.2 deletion affecting TBX6) and single-nucleotide variants (1 nonsense and 4 frame-shift mutations). However, the discordant intrafamilial phenotypes of 16p11.2 deletion carriers suggest that heterozygous TBX6 null mutation is insufficient to cause congenital scoliosis. We went on to identify a common TBX6 haplotype as the second risk allele in all 17 carriers of TBX6 null mutations (P<1.1×10−6). Replication studies involving additional persons with congenital scoliosis who carried a deletion affecting TBX6 confirmed this compound inheritance model. In vitro functional assays suggested that the risk haplotype is a hypomorphic allele. Hemivertebrae are characteristic of TBX6-associated congenital scoliosis.
Compound inheritance of a rare null mutation and a hypomorphic allele of TBX6 accounted for up to 11% of congenital scoliosis cases in the series that we analyzed.
PMCID: PMC4326244  PMID: 25564734
3.  MicroRNA-29a promotes colorectal cancer metastasis by regulating matrix metalloproteinase 2 and E-cadherin via KLF4 
Tang, W | Zhu, Y | Gao, J | Fu, J | Liu, C | Liu, Y | Song, C | Zhu, S | Leng, Y | Wang, G | Chen, W | Du, P | Huang, S | Zhou, X | Kang, J | Cui, L
British Journal of Cancer  2013;110(2):450-458.
Growing evidence suggests that miR-29a has an important role in regulating tumourigenesis and development of various types of cancer. However, the role and the underlying mechanism of miR-29a in colorectal cancer (CRC) remain largely unknown.
MiR-29a targeted gene was identified by the luciferase assay and western blot. MiR-29a function was analysed by invasion assays and the orthotopic transplantation mouse model. The miR-29a pathway was assayed by real-time PCR, western blot and chip analysis.
KLF4 was identified as a direct target gene of miR-29a. MiR-29a promoted CRC cell invasion, which was blocked by re-expression of KLF4. In addition, MMP2 was identified as a novel direct target of KLF4. Both miR-29a overexpression and KLF4 knockdown promoted MMP2 expression but inhibited E-cadherin expression. Furthermore, clinical data indicated that both miR-29a high expression and KLF4 mRNA low expression were associated with metastasis and poor prognosis in CRC patients, and KLF4 protein expression was inversely correlated with MMP2 but positively correlated with E-cad protein expression.
Increased expression of miR-29a promoted CRC metastasis by regulating MMP2/E-cad through direct targeting KLF4, which highlights the potential of the miR-29a inhibitor as a novel agent against CRC metastasis.
PMCID: PMC3899762  PMID: 24281002
miR-29a; colorectal cancer; metastasis; KLF4
4.  Corneal changes after a single session of selective laser trabeculoplasty for open-angle glaucoma 
Eye  2013;28(1):47-52.
To investigate the changes in endothelial cell count, central corneal thickness (CCT), and refractive error after a session of selective laser trabeculoplasty (SLT) for open angle glaucoma (OAG).
This prospective cohort study recruited 111 eyes of 66 consecutive subjects with OAG. Subjects received SLT to 360° of the trabecular meshwork. Endothelial cell count, CCT, and spherical equivalent were measured at baseline before SLT as well as at 1 week and 1 month post SLT. A repeated measure nested ANOVA with Tukey's multiple comparison test was performed to compare the outcome measures before and after SLT.
In 111 eyes of 66 subjects, the mean number of laser applications per treatment was 166.9±41.4 with a mean energy level of 1.0±0.07 mJ. The mean endothelial cell count decreased significantly from 2465.0±334.0 cells/mm2 at baseline to 2355.0±387.0 cells/mm2 at 1 week (P=0.0004) but increased to baseline levels at 1 month post SLT (2424.0±379.4 cells/mm2, P=0.3). The CCT, which decreased from a baseline of 549.4±37.6 to 543.9±40.2 μm at 1 week post SLT (P=0.02), also returned to the baseline level by 1 month (P=0.2). The spherical equivalent was static from baseline. A positive correlation was found between total laser energy and CCT at 1 month post treatment (r=0.3, P=0.005).
The transient reductions in endothelial cell count and CCT following SLT returned to baseline levels 1 month after the procedure. Patients undergoing SLT should be aware of the risk of potential corneal changes.
PMCID: PMC3890760  PMID: 24136571
selective laser trabeculplasty; endothelial cell count; central cornea thickness; spherical equivalent; cornea
5.  Point-of-care oral-based diagnostics 
Oral diseases  2011;17(8):745-752.
Many of the target molecules that reside in blood are also present in oral fluids, albeit at lower concentrations. Oral fluids are, however, relatively easy and safe to collect without the need for specialized equipment and training. Thus, oral fluids provide convenient samples for medical diagnostics. Recent advances in lab-on-a-chip technologies have made minute, fully integrated diagnostic systems practical for an assortment of point-of-care tests. Such systems can perform either immunoassays or molecular diagnostics outside centralized laboratories within time periods ranging from minutes to an hour. The article briefly reviews recent advances in devices for point-of-care testing with a focus on work that has been carried out by the authors as part of a NIH program.
PMCID: PMC4273652  PMID: 21521419
lab-on-a-chip; point-of-care testing; oral-based diagnostics; microfluidics
7.  Thalamic Post-Inhibitory Bursting Occurs in Patients with Organic Dystonia more often than Controls 
Brain research  2013;1541:81-91.
We now test the hypothesis that post-inhibitory bursting in the human pallidal receiving nucleus of the thalamus (ventral oral) mediates inhibitory pallido-thalamic transmission during dystonia. We have compared thalamic single neuron activity in nine patients with organic dystonia to that in a patient with psychogenic dystonia (Psyd) and in healthy waking monkeys.
In organic dystonia, EMG power is commonly concentrated at the lowest frequency of the smoothed autopower spectrum (0.39Hz). Therefore, segments of spike trains with a signal-to-noise ratio ≥ 2 at 0.39 Hz were termed dystonia frequency (DF) segments, which occurred more commonly during dystonia related to movement. Those with a SNR < 2 were termed non-dystonia frequency (nDF) segments, which are associated with spontaneous dystonia. We concentrated on nDF activity since neuronal activity in our controls was measured at rest. Neuronal spike trains were categorized into those with post-inhibitory bursts (G, grouped), with single spikes (NG, non-grouped), or with both single spikes and bursts (I, intermediate). nDF spike trains in ventral oral had more G category firing in dystonia than in controls. The burst rate and the pre-burst silent period in nDF firing of organic dystonia were consistently greater than those of both the monkeys and the patient with Psyd. The distribution of the pre-burst silent period was bimodal with a longer mode of approximately GABAb (gamma amino butyric acid receptor - type b) duration.
These results demonstrate distinct differences of post-inhibitory bursting in organic dystonia versus controls. The presence of inhibitory events consistent with GABAb duration suggests interventions for treatment of dystonia.
PMCID: PMC3889805  PMID: 24125808
dystonia; thalamus; single neuron analysis; low threshold spike bursts; thalamotomy
8.  A novel subset of helper T cells promotes immune responses by secreting GM-CSF 
Cell Death and Differentiation  2013;20(12):1731-1741.
Helper T cells are crucial for maintaining proper immune responses. Yet, they have an undefined relationship with one of the most potent immune stimulatory cytokines, granulocyte macrophage-colony-stimulating factor (GM-CSF). By depleting major cytokines during the differentiation of CD4+ T cells in vitro, we derived cells that were found to produce large amounts of GM-CSF, but little of the cytokines produced by other helper T subsets. By their secretion of GM-CSF, this novel subset of helper T cells (which we have termed ThGM cells) promoted the production of cytokines by other T-cell subtypes, including type 1 helper T cell (Th1), type 2 helper T cell (Th2), type 1 cytotoxic T cell (Tc1), type 2 cytotoxic T cell (Tc2), and naive T cells, as evidenced by the fact that antibody neutralization of GM-CSF abolished this effect. ThGM cells were found to be highly prone to activation-induced cell death (AICD). Inhibitors of TRAIL or granzymes could not block AICD in ThGM cells, whereas inhibition of FasL/Fas interaction partially rescued ThGM cells from AICD. Thus, ThGM cells are a novel subpopulation of T helper cells that produce abundant GM-CSF, exhibit exquisite susceptibility to apoptosis, and therefore play a pivotal role in the regulation of the early stages of immune responses.
PMCID: PMC3824596  PMID: 24076588
helper T cell; GM-CSF; apoptosis; cytokine
9.  Deficiency of Kruppel-like factor KLF4 in myeloid-derived suppressor cells inhibits tumor pulmonary metastasis in mice accompanied by decreased fibrocytes 
Oncogenesis  2014;3(11):e129-.
The importance of immunosuppressive myeloid-derived suppressor cells (MDSCs) bearing monocyte markers in tumor metastasis has been well established. Recently, it was reported that these cells possess phenotypic plasticity and differentiate into fibrocytes, very distinct cells that are precursors of tumorigenic myofibroblasts. However, the importance of this transdifferentiation in tumor metastasis has not been explored. Here, we describe the role of MDSC-derived fibrocytes in tumor metastasis that is regulated by Kruppel-like factor 4 (KLF4), a transcription factor that is critical to monocyte differentiation and to promotion of cancer development. Using mouse metastasis models of melanoma and breast cancer, we found that KLF4 knockout was associated with significantly reduced pulmonary metastasis, which was accompanied by decreased populations of MDSCs, fibrocytes and myofibroblasts in the lung. Cause-effect studies by adoptive transfer revealed that KLF4 deficiency in MDSCs led to significantly reduced lung metastasis that was associated with fewer MDSC-derived fibrocytes and myofibroblasts. Mechanistically, KLF4 deficiency significantly compromised the generation of fibrocytes from MDSCs in vitro. During this process, KLF4 expression levels were tightly linked with those of fibroblast-specific protein-1 (FSP-1), deficiency of which resulted in no metastasis in mice as has been previously reported. In addition, KLF4 bound directly to the FSP-1 promoter as determined by chromatin immunoprecipitation and overexpression of KLF4 increased the FSP-1 promoter activities. Taken together, our results suggest that MDSCs not only execute their immunosuppressive function to promote metastatic seeding as reported before, but also boost metastatic tumor growth after they adopt a fibrocyte fate. Therefore, KLF4-mediated fibrocyte generation from MDSCs may represent a novel mechanism of MDSCs contributing to tumor metastasis and supports the feasibility of inhibiting KLF4 or FSP-1 to prevent tumor metastasis.
PMCID: PMC4259966  PMID: 25417726
10.  Probing Stochastic Nano-Scale Inelastic Events in Stressed Amorphous Metal 
Scientific Reports  2014;4:6699.
One fundamental yet longstanding issue in materials science is how local inelasticity arises within an amorphous structure before yielding occurs. Although many possible scenarios were postulated or predicted by theories and simulations,however, direct experimental evidence has been lacking today due to the lack of a sensitive way to detect nano-scale inelasticity. Through the carefully designed microcompression method as coupled with the state-of-art nano-scale electric resistance measurement, we here unfold a stochastic inelastic deformation process in a Zr-based metallic glass, which takes place via the recurrence of two types of short-lived inelastic events causing structural damage and recovery, respectively, prior to yielding. Our current findings reveal that these stochastic events not only self-organize into sub-critical events due to elastic coupling, but also compete with each other in a way that enables the whole amorphous structure to self-heal as well as to sustain local damage.
PMCID: PMC4204032  PMID: 25331932
11.  Pro-neural miR-128 is a glioma tumor suppressor that targets mitogenic kinases 
Oncogene  2011;31(15):1884-1895.
MicroRNAs (miRNAs) carry out post-transcriptional control of a multitude of cellular processes. Aberrant expression of miRNA can lead to diseases, including cancer. Gliomas are aggressive brain tumors that are thought to arise from transformed glioma-initiating neural stem cells (giNSCs). With the use of giNSCs and human glioblastoma cells, we investigated the function of miRNAs in gliomas. We identified pro-neuronal miR-128 as a candidate glioma tumor suppressor miRNA. Decreased expression of miR-128 correlates with aggressive human glioma subtypes. With a combination of molecular, cellular and in vivo approaches, we characterize miR-128’s tumor suppressive role. miR-128 represses giNSC growth by enhancing neuronal differentiation. miR-128 represses growth and mediates differentiation by targeting oncogenic receptor tyrosine kinases (RTKs) epithelial growth factor receptor and platelet-derived growth factor receptor-α. Using an autochthonous glioma mouse model, we demonstrated that miR-128 repressed gliomagenesis. We identified miR-128 as a glioma tumor suppressor that targets RTK signaling to repress giNSC self-renewal and enhance differentiation.
PMCID: PMC4160048  PMID: 21874051
microRNA; glioma stem cells; miR-128; EGFR; PDGFRα
12.  Temporally Overlapped but Uncoupled Motions in Dihydrofolate Reductase Catalysis 
Biochemistry  2013;52(32):5332-5334.
Temporal correlations between protein motions and enzymatic reactions are often interpreted as evidence for catalytically important motions. Using dihydrofolate reductase as a model system, we show that there are many protein motions that temporally overlapped with the chemical reaction, and yet they do not exhibit the same kinetic behaviors (KIE and pH dependence) as the catalyzed chemical reaction. Thus, despite the temporal correlation, these motions are not directly coupled to the chemical transformation, and they might represent a different part of the catalytic cycle or simply be the product of the intrinsic flexibility of the protein.
PMCID: PMC3779903  PMID: 23883151
To determine if sarcopenia modulates the response to a physical activity intervention in functionally limited older adults.
Secondary analysis of a randomized controlled trial.
Three academic centers.
Elders aged 70 to 89 years at risk for mobility disability who underwent dual-energy x-ray absorptiometry (DXA) for body composition at enrollment and follow-up at twelve months (N = 177).
Subjects participated in a physical activity program (PA) featuring aerobic, strength, balance, and flexibility training, or a successful aging (SA) educational program about healthy aging.
Sarcopenia as determined by measuring appendicular lean mass and adjusting for height and total body fat mass (residuals method), Short Physical Performance Battery score (SPPB), and gait speed determined on 400 meter course.
At twelve months, sarcopenic and non-sarcopenic subjects in PA tended to have higher mean SPPB scores (8.7±0.5 and 8.7±0.2 points) compared to sarcopenic and non-sarcopenic subjects in SA (8.3±0.5 and 8.4±0.2 points, p = 0.24 and 0.10), although the differences were not statistically significant. At twelve months, faster mean gait speeds were observed in PA: 0.93±0.4 and 0.95±0.03 meters/second in sarcopenic and non-sarcopenic PA subjects, and 0.89±0.4 and 0.91±0.03 meters/second in sarcopenic and non-sarcopenic SA subjects (p = 0.98 and 0.26), although not statistically significant. There was no difference between the sarcopenic and non-sarcopenic groups in intervention adherence or number of adverse events.
These data suggest that older adults with sarcopenia, who represent a vulnerable segment of the elder population, are capable of improvements in physical performance after a physical activity intervention.
PMCID: PMC4111145  PMID: 24402391
Sarcopenia; physical activity; gait speed; short physical performance battery
14.  Association between tuberculosis infections and non-pulmonary malignancies: a nationwide population-based study 
British Journal of Cancer  2013;109(1):229-234.
In addition to lung cancers, tuberculosis infections have been associated with increased risk of non-pulmonary malignancies in case reports. Our population-based study employed standardized incidence ratios (SIRs) to systemically survey non-pulmonary cancer risks after tuberculosis infections.
Data of patients who had newly diagnosed tuberculosis, were aged 20 years or older, and had no prior cancer or tuberculosis were sampled from the Taiwan National Health Insurance database between 2000 and 2010. SIRs compared cancer incidence in patients with tuberculosis infections to the general population. SIRs of specific cancers were further analyzed with respect to gender and time after tuberculosis infections.
After a follow-up period of 28 866 person–years, 530 tuberculosis cases developed cancers compared with 256 cases in the general populations (2.07, 95% confidence interval (CI), 1.90–2.26). The SIR of non-pulmonary malignancies was also increased (1.71, 95% CI, 1.54–1.90). For males, SIRs were increased within 1 year after tuberculosis diagnosis for the following cancers: head and neck, esophageal, colorectal, liver, lung, melanomas, and Hodgkin's disease. SIRs were increased for liver, biliary, lung, and bladder cancers beyond the first year after tuberculosis diagnosis. For females, SIRs were increased for leukemia, esophageal, and lung cancers within the first year, and only for leukemia beyond 1 year post diagnosis.
Having found increased risks of several cancers that differ with gender and time after tuberculosis diagnosis, physicians may consider these factors in patients following tuberculosis diagnosis.
PMCID: PMC3708573  PMID: 23652313
tuberculosis infections; standardized incidence ratios
15.  Evidence for a motor gamma-band network governing response interference✰ 
NeuroImage  2013;74:10.1016/j.neuroimage.2013.02.013.
The gamma-band response is thought to represent a key neural signature of information processing in the human brain. These brain signals have been associated with a variety of sensory modalities (vision, sensation, and audition) and also following basic motor responses, yet the functional significance of the motor gamma-band response remains unclear. We used the Multi-Source Interference Task (MSIT) to assess the sensitivity of these cortical motor gamma-band rhythms to stimuli producing response interference. We recorded MEG from adult participants (N=24) during MSIT task performance and compared motor gamma-band activity on Control and Interference trials.
Reaction time on MSIT Interference trials was significantly longer (∼0.2 s) for all subjects. Response interference produced a significant increase in motor gamma-band activity including ∼0.5 s sustained increase in gamma-band activity from contralateral primary motor area directly preceding the response. In addition, activation of increased right Inferior Frontal Gyrus (R-IFG) was observed at gamma-band frequencies ∼0.2 s prior to the button press response. Post-hoc analysis of R-IFG gamma-band activity was observed to correlate with reaction time increases to response interference.
Our study is the first to record MEG during MSIT task performance. We observed novel activity of the motor gamma-band on interference trials which was sustained prior to the response and in novel locations including contralateral (BA6), and R-IFG. Our results support the idea that R-IFG is specialized structure for response control that also functions at gamma-band frequencies. Together, these data provide evidence for a motor gamma-band network for response selection and maintenance of planned behavior.
PMCID: PMC3817211  PMID: 23454050
MEG; Magnetoencephalography; Motor cortex; amma-band response; Multi-source interference task (MSIT); Response interference
16.  Erlotinib derivative inhibits hepatocellular carcinoma by targeting CIP2A to reactivate protein phosphatase 2A 
Cell Death & Disease  2014;5(7):e1359-.
Protein phosphatase 2A (PP2A) is a tumor suppressor, which is functionally defective in various cancers. Previously, we found that PP2A activity determined the anticancer effect of bortezomib and erlotinib in hepatocellular carcinoma (HCC) cells. Here, we tested a novel erlotinib derivative, TD52, in four HCC cell lines, PLC5, Huh-7, Hep3B and Sk-Hep1. Using MTT and flow cytometry, we showed that TD52 had more potent apoptotic effects than erlotinib in HCC cells. TD52-induced apoptosis was associated with dose- and time- dependent reactivation of PP2A and downregulation of cancerous inhibitor of protein phosphatase 2A (CIP2A) and p-Akt. Inhibition of PP2A or ectopic expression of CIP2A or Akt in PLC5 cells abolished the effects of TD52. Furthermore, we demonstrated that TD52 affected the binding of Elk-1 to the proximal promoter of the CIP2A gene, thus downregulating transcription of CIP2A. Importantly, TD52-induced tumor inhibition was associated with reactivation of PP2A and downregulation of CIP2A and p-Akt in vivo. In conclusion, we found that enhancement of PP2A activity by inhibition of CIP2A determines the apoptotic effect induced by TD52. Our findings disclose the therapeutic mechanism of this novel targeted agent, and suggest the therapeutic potential and feasibility of developing PP2A enhancers as a novel anticancer strategy.
PMCID: PMC4123111  PMID: 25077545
17.  Synergistic effect of trichostatin A and scriptaid on the development of cloned rabbit embryos 
Theriogenology  2013;79(9):1284-1293.
The first successful rabbit SCNT was achieved more than one decade ago, yet rabbits remain one of the most difficult species to clone. The present study was designed to evaluate the effects of two histone deacetylase inhibitors (HDACi), namely trichostatin A (TSA) and scriptaid (SCP), on cloning efficiency in rabbits. The in vitro development, acetylation levels of histone H4 lysine 5 (H4K5ac), and Oct-4 protein expression patterns of cloned embryos were systemically examined after various HDACi treatments. Supplementation of TSA (50 nM) or SCP (250 nM) in the culture medium for 6 h improved blastocyst development rates of cloned embryos compared to treatment without HDACi. The combined treatment with TSA (50 nM) and SCP (250 nM) further enhanced morula (58.6%) and blastocyst (49.4%) rates in vitro. More importantly, compared to single HDACi treatments, embryos with the combined treatment had a higher level of H4K5ac and an increased total cell number (203.7±14.4 vs 158.9±9.0 or 162.1±8.2, P<0.05) with better Oct-4 expression pattern in hatching blastocysts, indicating substantially improved embryo quality. This was apparently the first report regarding Oct-4 expression in cloned rabbit embryos. We inferred that the majority of cloned rabbit embryos had an aberrant ICM structure accompanied with abnormal spatial distribution of Oct-4 signals. This study demonstrated a synergistic effect of TSA and SCP treatments on cloned rabbit embryos, which may be useful to improve cloning efficiency in rabbits.
PMCID: PMC3677057  PMID: 23566670
18.  Non-viral FoxM1 gene delivery to hepatocytes enhances liver repopulation 
Cell Death & Disease  2014;5(5):e1252-.
Hepatocyte transplantation as a substitute strategy of orthotopic liver transplantation is being studied for treating end-stage liver diseases. Several technical hurdles must be overcome in order to achieve the therapeutic liver repopulation, such as the problem of insufficient expansion of the transplanted hepatocytes in recipient livers. In this study, we analyzed the application of FoxM1, a cell-cycle regulator, to enhance the proliferation capacity of hepatocytes. The non-viral sleeping beauty (SB) transposon vector carrying FoxM1 gene was constructed for delivering FoxM1 into the hepatocytes. The proliferation capacities of hepatocytes with FoxM1 expression were examined both in vivo and in vitro. Results indicated that the hepatocytes with FoxM1 expression had a higher proliferation rate than wild-type (WT) hepatocytes in vitro. In comparison with WT hepatocytes, the hepatocytes with FoxM1 expression had an enhanced level of liver repopulation in the recipient livers at both sub-acute injury (fumaryl acetoacetate hydrolase (Fah)–/– mice model) and acute injury (2/3 partial hepatectomy mice model). Importantly, there was no increased risk of tumorigenicity with FoxM1 expression in recipients even after serial transplantation. In conclusion, expression of FoxM1 in hepatocytes enhanced the capacity of liver repopulation without inducing tumorigenesis. FoxM1 gene delivered by non-viral SB vector into hepatocytes may be a viable approach to promote therapeutic repopulation after hepatocyte transplantation.
PMCID: PMC4047909  PMID: 24853430
FoxM1; sleeping beauty transposon; non-viral; hepatocyte transplantation; liver repopulation
19.  IRE1a constitutes a negative feedback loop with BMP2 and acts as a novel mediator in modulating osteogenic differentiation 
Cell Death & Disease  2014;5(5):e1239-.
Bone morphogenetic protein 2 (BMP2) is known to activate unfolded protein response (UPR) signaling molecules, such as BiP (IgH chain-binding protein), PERK (PKR-like ER-resistant kinase), and IRE1α. Inositol-requiring enzyme-1a (IRE1a), as one of three unfolded protein sensors in UPR signaling pathways, can be activated during ER stress. Granulin-epithelin precursor (GEP) is an autocrine growth factor that has been implicated in embryonic development, tissue repair, tumorigenesis, and inflammation. However, the influence on IRE1a in BMP2-induced osteoblast differentiation has not yet been elucidated. Herein we demonstrate that overexpression of IRE1a inhibits osteoblast differentiation, as revealed by reduced activity of alkaline phosphatase (ALP) and osteocalcin; however, knockdown of IRE1a via the RNAi approach stimulates osteoblastogenesis. Mechanistic studies revealed that the expression of IRE1a during osteoblast was a consequence of JunB transcription factor binding to several AP1 sequence (TGAG/CTCA) in the 5′-flanking regulatory region of the IRE1a gene, followed by transcription. In addition, GEP induces IRE1a expressions and this induction of IRE1a by GEP depends on JunB. Furthermore, IRE1a inhibition of GEP-induced osteoblastogenesis relies on JunB. Besides, GEP is required for IRE1a inhibition of BMP2-induced bone formation. Collectively, these findings demonstrate that IRE1a negatively regulates BMP2-induced osteoblast differentiation and this IRE1a inhibition effect depends on GEP growth factor. Thus, IRE1a, BMP2, GEP growth factor, and JunB transcription factor form a regulatory loop and act in concert in the course of osteoblastogenesis.
PMCID: PMC4047903  PMID: 24853417
inositol-requiring enzyme-1a; osteoblastogenesis; GEP; BMP2; unfolded protein response
20.  Superior Tensile Ductility in Bulk Metallic Glass with Gradient Amorphous Structure 
Scientific Reports  2014;4:4757.
Over centuries, structural glasses have been deemed as a strong yet inherently ‘brittle’ material due to their lack of tensile ductility. However, here we report bulk metallic glasses exhibiting both a high strength of ~2 GPa and an unprecedented tensile elongation of 2–4% at room temperature. Our experiments have demonstrated that intense structural evolution can be triggered in theses glasses by the carefully controlled surface mechanical attrition treatment, leading to the formation of gradient amorphous microstructures across the sample thickness. As a result, the engineered amorphous microstructures effectively promote multiple shear banding while delay cavitation in the bulk metallic glass, thus resulting in superior tensile ductility. The outcome of our research uncovers an unusual work-hardening mechanism in monolithic bulk metallic glasses and demonstrates a promising yet low-cost strategy suitable for producing large-sized, ultra-strong and stretchable structural glasses.
PMCID: PMC3996486  PMID: 24755683
21.  The atomic-scale mechanism for the enhanced glass-forming-ability of a Cu-Zr based bulk metallic glass with minor element additions 
Scientific Reports  2014;4:4648.
It is known that the glass forming-ability (GFA) of bulk metallic glasses (BMGs) can be greatly enhanced via minor element additions. However, direct evidence has been lacking to reveal its structural origin despite different theories hitherto proposed. Through the high-resolution transmission-electron-microscopy (HRTEM) analysis, here we show that the content of local crystal-like orders increases significantly in a Cu-Zr-Al BMG after a 2-at% Y addition. Contrasting the previous studies, our current results indicate that the formation of crystal-like order at the atomic scale plays an important role in enhancing the GFA of the Cu-Zr-Al base BMG.
PMCID: PMC3983660  PMID: 24721927
22.  Research on Dynamic Routing Mechanisms in Wireless Sensor Networks 
The Scientific World Journal  2014;2014:165694.
WirelessHART is the most widely applied standard in wireless sensor networks nowadays. However, it does not provide any dynamic routing mechanism, which is important for the reliability and robustness of the wireless network applications. In this paper, a collection tree protocol based, dynamic routing mechanism was proposed for WirelessHART network. The dynamic routing mechanism was evaluated through several simulation experiments in three aspects: time for generating the topology, link quality, and stability of network. Besides, the data transmission efficiency of this routing mechanism was analyzed. The simulation and evaluation results show that this mechanism can act as a dynamic routing mechanism for the TDMA-based wireless sensor network.
PMCID: PMC4005053  PMID: 24982927
23.  Loss of TACSTD2 contributed to squamous cell carcinoma progression through attenuating TAp63-dependent apoptosis 
Wang, F | Liu, X | Yang, P | Guo, L | Liu, C | Li, H | Long, S | Shen, Y | Wan, H
Cell Death & Disease  2014;5(3):e1133-.
Tumor-associated calcium signal transducer 2 (TACSTD2), a calcium signal transducer, is universally expressed in stratified squamous epithelia of many organs, including skin, esophagus and cervix. Although TACSTD2, was reported to be overexpressed in many epithelial tumors, which has increased interest in using it as a molecular target for cancer therapy, the role of TACSTD2 in carcinogenesis of squamous cell carcinoma (SCC) is largely unclear and controversial. To explore the role of TACSTD2, temporal-spatial expression of TACSTD2 was analyzed in both normal and SCC tissues. Our data demonstrate that Tacstd2 expression and membrane localization are tightly associated with stratified epithelial homeostasis, while loss of TACSTD2 was identified in poorly differentiated SCC tissues collected from cervix, esophagus, head and neck. Gradual loss of TACSTD2 was correlated with stepwise progression of SCC. Consistent with these in vivo observations, our data show that inhibition of Tacstd2 expression significantly inhibited chemotherapeutic reagent-induced apoptosis, and TACSTD2 regulated apoptotic gene expression through P63 containing the transactivation domain (TAp63). These findings indicated that loss of TACSTD2 could promote SCC progression and treatment resistance through attenuating chemotherapeutic reagent-induced apoptosis through TAp63, and TACSTD2 could be used as a marker for pathological grading of SCC.
PMCID: PMC3973208  PMID: 24651436
TACSTD2; squamous cell carcinoma; apoptosis; TAp63; tumor progression
24.  MiRNA-210 modulates a nickel-induced cellular energy metabolism shift by repressing the iron–sulfur cluster assembly proteins ISCU1/2 in Neuro-2a cells 
He, M | Lu, Y | Xu, S | Mao, L | Zhang, L | Duan, W | Liu, C | Pi, H | Zhang, Y | Zhong, M | Yu, Z | Zhou, Z
Cell Death & Disease  2014;5(2):e1090-.
The cellular energy metabolism shift, characterized by the inhibition of oxidative phosphorylation (OXPHOS) and enhancement of glycolysis, is involved in nickel-induced neurotoxicity. MicroRNA-210 (miR-210) is regulated by hypoxia-inducible transcription factor-1α (HIF-1α) under hypoxic conditions and controls mitochondrial energy metabolism by repressing the iron–sulfur cluster assembly protein (ISCU1/2). ISCU1/2 facilitates the assembly of iron–sulfur clusters (ISCs), the prosthetic groups that are critical for mitochondrial oxidation-reduction reactions. This study aimed to investigate whether miR-210 modulates alterations in energy metabolism after nickel exposure through suppressing ISCU1/2 and inactivating ISCs-containing metabolic enzymes. We determined that NiCl2 exposure leads to a significant accumulation of HIF-1α, rather than HIF-1β, in Neuro-2a cells. The miR-210 overexpression and ISCU1/2 downregulation was observed in a dose- and time-dependent manner. The gain-of-function and loss-of-dysfunction assays revealed that miR-210 mediated the ISCU1/2 suppression, energy metabolism alterations, and ISC-containing metabolic enzyme inactivation after nickel exposure. In addition, the impact of miR-210 on ISC-containing metabolic enzymes was independent from cellular iron regulation. Overall, these data suggest that repression of miR-210 on ISCU1/2 may contribute to HIF-1α-triggered alterations in energy metabolism after nickel exposure. A better understanding of how nickel impacts cellular energy metabolism may facilitate the elucidation of the mechanisms by which nickel affects the human health.
PMCID: PMC3944272  PMID: 24577088
nickel; energy metabolism shift; miR-210; ISCU1/2; glycolysis

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