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1.  Highly Constrained Backprojection for Time-Resolved MRI 
Recent work in k-t BLAST and undersampled projection angiography has emphasized the value of using training data sets obtained during the acquisition of a series of images. These techniques have used iterative algorithms guided by the training set information to reconstruct time frames sampled at well below the Nyquist limit. We present here a simple non-iterative unfiltered backprojection algorithm that incorporates the idea of a composite image consisting of portions or all of the acquired data to constrain the backprojection process. This significantly reduces streak artifacts and increases the overall SNR, permitting decreased numbers of projections to be used when acquiring each image in the image time series. For undersampled 2D projection imaging applications, such as cine phase contrast (PC) angiography, our results suggest that the angular undersampling factor, relative to Nyquist requirements, can be increased from the present factor of 4 to about 100 while increasing SNR per individual time frame. Results are presented for a contrast-enhanced PR HYPR TRICKS acquisition in a volunteer using an angular undersampling factor of 75 and a TRICKS temporal undersampling factor of 3 for an overall undersampling factor of 225.
doi:10.1002/mrm.20772
PMCID: PMC2366054  PMID: 16342275
time resolved MRI; constrained backprojection; undersampled data; ultra-fast imaging; acceleration factors
2.  Draft Genome Sequence of Clostridium sp. Strain Ade.TY, a New Biohydrogen- and Biochemical-Producing Bacterium Isolated from Landfill Leachate Sludge 
Genome Announcements  2014;2(2):e00078-14.
Clostridium sp. strain Ade.TY is potentially a new biohydrogen-producing species isolated from landfill leachate sludge. Here we present the assembly and annotation of its genome, which may provide further insights into its gene interactions for efficient biohydrogen production.
doi:10.1128/genomeA.00078-14
PMCID: PMC3945496  PMID: 24604640
3.  Helicobacter pylori sensitizes TNF-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis in human gastric epithelial cells through regulation of FLIP 
Cell Death & Disease  2014;5(3):e1109-.
Helicobacter pylori (H. pylori) infection is associated with chronic gastritis, peptic ulcer and gastric cancer. Apoptosis induced by microbial infections is implicated in the pathogenesis of H. pylori infection. Here we show that human gastric epithelial cells sensitized to H. pylori confer susceptibility to TRAIL-mediated apoptosis via modulation of death receptor signaling. Human gastric epithelial cells are intrinsically resistant to TRAIL-mediated apoptosis. The induction of TRAIL sensitivity by H. pylori is dependent on the activation of caspase-8 and its downstream pathway. H. pylori induces caspase-8 activation via enhanced assembly of the TRAIL death-inducing signaling complex (DISC) through downregulation of cellular FLICE-inhibitory protein (FLIP). Overexpression of FLIP abolished the H. pylori-induced TRAIL sensitivity in human gastric epithelial cells. Our study thus demonstrates that H. pylori induces sensitivity to TRAIL apoptosis by regulation of FLIP and assembly of DISC, which initiates caspase activation, resulting in the breakdown of resistance to apoptosis, and provides insight into the pathogenesis of gastric damage in Helicobacter infection. Modulation of host apoptosis signaling by bacterial interaction adds a new dimension to the pathogenesis of Helicobacter.
doi:10.1038/cddis.2014.81
PMCID: PMC3973194  PMID: 24603337
apoptosis signaling; DISC; FLIP; Helicobacter pylori; TRAIL
4.  Inhibiting αv Integrins Decreases the Malignant Characteristics of Medulloblastoma 
Object
Hypoxia induces an aggressive phenotype in some brain tumors in part due to hypoxia inducible factor 1α (HIF-1α) and integrin expression. The importance of hypoxia in medulloblastoma is unclear and the interaction of HIF-1α and c-Myc in medulloblastoma has not been explored. The objective of this project was to determine if hypoxia induces an aggressive phenotype in human medulloblastoma cells that constitutively express high (D283 Med) or low (DAOY) levels of c-Myc and to determine if blocking αv integrins with the monoclonal antibody, intetumumab, inhibits hypoxia-induced cellular stress responses.
Methods
Cells were grown at 21% and 1% O2 and in the presence or absence of intetumumab. Measures of malignancy evaluated included cell proliferation, cell migration, and expression of vascular endothelial growth factor (VEGF), αv integrins, HIF-1α, and c-Myc.
Results
Both cell lines robustly expressed αv integrins. Hypoxic DAOY cells had significantly increased proliferation compared to normoxic controls (P < 0.05) whereas D283 Med cells did not. Both cell lines exhibited a dose-dependent decrease in proliferation when treated with intetumumab, (P < 0.05). Hypoxia did not increase DAOY migration. Regardless, intetumumab significantly inhibited migration at both oxygen conditions (P < 0.05). Intetumumab significantly decreased VEGF levels in DAOY cells at both oxygen conditions (P < 0.05) and in normoxic D283 cells (P < 0.01). Neither cell line had increased HIF-1α expression in response to hypoxia. However, hypoxic D283 Med cells grown in the presence of intetumumab demonstrated significantly decreased c-Myc expression (P < 0.05).
Conclusions
Hypoxia did not clearly induce a more aggressive phenotype in medulloblastoma cells. Despite this, intetumumab decreased medulloblastoma cell proliferation and migration and variably decreased VEGF and c-Myc expression in hypoxic conditions. Targeting αv integrins represents a promising potential adjuvant modality in the treatment of medulloblastoma, particularly subtypes that metastasize and overexpress VEGF and c-Myc.
doi:10.3171/2012.9.PEDS12268
PMCID: PMC3709582  PMID: 23082872
medulloblastoma; intetumumab; αv integrin; hypoxia; c-Myc; HIF-1α
5.  Strategy to Control Type I Error Increases Power to Identify Genetic Variation Using the Full Biological Trajectory 
Genetic epidemiology  2013;37(5):10.1002/gepi.21733.
Genome-wide association studies have been successful in identifying loci that underlie continuous traits measured at a single time point. To additionally consider continuous traits longitudinally, it is desirable to look at SNP effects at baseline and over time using linear-mixed effects models. Estimation and interpretation of two coefficients in the same model raises concern regarding the optimal control of type I error. To investigate this issue, we calculate type I error and power under an alternative for joint tests, including the two degree of freedom likelihood ratio test, and compare this to single degree of freedom tests for each effect separately at varying alpha levels. We show which joint tests are the optimal way to control the type I error and also illustrate that information can be gained by joint testing in situations where either or both SNP effects are underpowered. We also show that closed form power calculations can approximate simulated power for the case of balanced data, provide reasonable approximations for imbalanced data, but overestimate power for complicated residual error structures. We conclude that a two degree of freedom test is an attractive strategy in a hypothesis-free genome-wide setting and recommend its use for genome-wide studies employing linear-mixed effects models.
doi:10.1002/gepi.21733
PMCID: PMC3877575  PMID: 23633177
linear-mixed effects model; genome-wide association study; longitudinal data; power and type I error calculations
6.  Contralateral De Novo Intraosseous Arteriovenous Malformation in a Child with Arteriovenous Malformation of Mandible Treated by Endovascular Embolotherapy 
Interventional Neuroradiology  2012;18(4):484-489.
Summary
We describe our experience of the development of contralateral de novo intraosseous AVMs in a ten-year-old girl with AVMs of the mandible who underwent endovascular embolotherapy. She initially presented with intermittent oral bleeding. Computed tomography and digital subtraction angiography demonstrated intraosseous AVMs within the right mandible. The AVMs were treated by transosseous direct-puncture and transarterial embolization with Guglielmi detachable coils and n-butyl cyanoacrylate glue. However, de novo intraosseous AVMs developed within the previously healthy contralateral mandible and resulted in dangerous oral bleeding. Therefore, we suggest regular follow-up and prompt retreatment of any residual mandibular AVMs in patients undergoing endovascular or surgical treatment to prevent subsequent development of “secondary” AVMs and life-threatening oral bleeding.
PMCID: PMC3520563  PMID: 23217644
mandible, arteriovenous malformation, transarterial embolization, transosseous embolization
7.  Designing novel bulk metallic glass composites with a high aluminum content 
Scientific Reports  2013;3:3353.
The long-standing challenge for forming Al-based BMGs and their matrix composites with a critical size larger than 1 mm have not been answered over the past three decades. In this paper, we reported formation of a series of BMG matrix composites which contain a high Al content up to 55 at.%. These composites can be cast at extraordinarily low cooling rates, compatible with maximum rod diameters of over a centimetre in copper mold casting. Our results indicate that proper additions of transition element Fe which have a positive heat of mixing with the main constituents La and Ce can appreciably improve the formability of the BMG matrix composites by suppressing the precipitation of Al(La,Ce) phase resulted from occurrence of the phase separation. However, the optimum content of Fe addition is strongly dependant on the total amount of the Al content in the Al-(CoCu)-(La,Ce) alloys.
doi:10.1038/srep03353
PMCID: PMC3842084  PMID: 24284800
8.  Using Multidimensional Mutual Information to Prioritize Mammographic Features for Breast Cancer Diagnosis 
AMIA Annual Symposium Proceedings  2013;2013:1534-1543.
The goal of this study was to demonstrate that information theory could be used to prioritize mammographic features to efficiently stratify the risk of breast cancer. We compared two approaches, Single-dimensional Mutual Information (SMI), which ranks features based on mutual information of features with outcomes without considering dependency of other features, and Multidimensional Mutual Information (MMI), which ranks features by considering dependency. To evaluate these approaches, we calculated area under the ROC curve for Bayesian networks trained and tested on features ranked by each approach. We found that both approaches were able to stratify mammograms by risk, but MMI required fewer features (ten vs. thirteen). MMI-based rankings may have greater clinical utility; a smaller set of features allows radiologists to focus on those findings with the highest yield and in the future may help improve mammography workflow.
PMCID: PMC3900164  PMID: 24551425
9.  Targeting αV-integrins decreased metastasis and increased survival in a nude rat breast cancer brain metastasis model 
Journal of neuro-oncology  2012;110(1):27-36.
Brain metastases commonly occur in patients with breast, lung and melanoma systemic cancers. The anti-αV integrin monoclonal antibody intetumumab binds cell surface proteins important for adhesion, invasion and angiogenesis in the metastatic cascade. The objective of this study was to investigate the anti-metastatic effect of intetumumab in a hematogenous breast cancer brain metastasis model. Female nude rats received intra-carotid infusion of human brain-seeking metastatic breast cancer cells (231BR-HER2) and were randomly assigned into 4 groups: 1) control; 2) intetumumab mixed with cells in vitro 5 min before infusion without further treatment; 3) intetumumab intravenously 4 h before and weekly after cell infusion; 4) intetumumab intravenously weekly starting 7 d after cell infusion. Brain metastases were detected by magnetic resonance imaging (MRI) and immunohistochemistry. Comparisons were made using the Kruskal-Wallis test and Dunnett’s test. Survival times were estimated using Kaplan-Meier analysis. All control rats with brain tissue available for histology (9 of 11 rats) developed multiple brain metastases (median=14). Intetumumab treatment either in vitro prior to cell infusion or intravenous before or after cell infusion prevented metastasis formation on MRI and decreased the number of metastases on histology (median=2, p=0.0055), including 30% of animals without detectable tumors at the end of the study. The overall survival was improved by intetumumab compared to controls (median 77+ versus 52 d, p=0.0277). Our results suggest that breast cancer patients at risk of metastases might benefit from early intetumumab treatment.
doi:10.1007/s11060-012-0942-0
PMCID: PMC3726254  PMID: 22842979
integrin; intetumumab; breast cancer; brain metastasis; MRI
10.  Loss of TAK1 increases cell traction force in a ROS-dependent manner to drive epithelial–mesenchymal transition of cancer cells 
Cell Death & Disease  2013;4(10):e848-.
Epithelial–mesenchymal transition (EMT) is a crucial step in tumor progression, and the TGFβ–SMAD signaling pathway as an inductor of EMT in many tumor types is well recognized. However, the role of non-canonical TGFβ–TAK1 signaling in EMT remains unclear. Herein, we show that TAK1 deficiency drives metastatic skin squamous cell carcinoma earlier into EMT that is conditional on the elevated cellular ROS level. The expression of TAK1 is consistently reduced in invasive squamous cell carcinoma biopsies. Tumors derived from TAK1-deficient cells also exhibited pronounced invasive morphology. TAK1-deficient cancer cells adopt a more mesenchymal morphology characterized by higher number of focal adhesions, increase surface expression of integrin α5β1 and active Rac1. Notably, these mutant cells exert an increased cell traction force, an early cellular response during TGFβ1-induced EMT. The mRNA level of ZEB1 and SNAIL, transcription factors associated with mesenchymal phenotype is also upregulated in TAK1-deficient cancer cells compared with control cancer cells. We further show that TAK1 modulates Rac1 and RhoA GTPases activities via a redox-dependent downregulation of RhoA by Rac1, which involves the oxidative modification of low-molecular weight protein tyrosine phosphatase. Importantly, the treatment of TAK1-deficient cancer cells with Y27632, a selective inhibitor of Rho-associated protein kinase and antioxidant N-acetylcysteine augment and hinders EMT, respectively. Our findings suggest that a dysregulated balance in the activation of TGFβ–TAK1 and TGFβ–SMAD pathways is pivotal for TGFβ1-induced EMT. Thus, TAK1 deficiency in metastatic cancer cells increases integrin:Rac-induced ROS, which negatively regulated Rho by LMW-PTP to accelerate EMT.
doi:10.1038/cddis.2013.339
PMCID: PMC3824649  PMID: 24113182
reactive oxygen species; cell traction force; epithelial–mesenchymal transition
11.  Quercetin postconditioning attenuates myocardial ischemia/reperfusion injury in rats through the PI3K/Akt pathway 
Quercetin (Que), a plant-derived flavonoid, has multiple benefical actions on the cardiovascular system. The current study investigated whether Que postconditioning has any protective effects on myocardial ischemia/reperfusion (I/R) injury in vivo and its potential cardioprotective mechanisms. Male Sprague-Dawley rats were randomly allocated to 5 groups (20 animals/group): sham, I/R, Que postconditioning, Que+LY294002 [a phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway inhibitor], and LY294002+I/R. I/R was produced by 30-min coronary occlusion followed by 2-h reperfusion. At the end of reperfusion, myocardial infarct size and biochemical changes were compared. Apoptosis was evaluated by both TUNEL staining and measurement of activated caspase-3 immunoreactivity. The phosphorylation of Akt and protein expression of Bcl-2 and Bax were determined by Western blotting. Que postconditioning significantly reduced infarct size and serum levels of creatine kinase and lactate dehydrogenase compared with the I/R group (all P<0.05). Apoptotic cardiomyocytes and caspase-3 immunoreactivity were also suppressed in the Que postconditioning group compared with the I/R group (both P<0.05). Akt phosphorylation and Bcl-2 expression increased after Que postconditioning, but Bax expression decreased. These effects were inhibited by LY294002. The data indicate that Que postconditioning can induce cardioprotection by activating the PI3K/Akt signaling pathway and modulating the expression of Bcl-2 and Bax proteins.
doi:10.1590/1414-431X20133036
PMCID: PMC3854307  PMID: 24068165
Ischemia and reperfusion; Quercetin; Postconditioning; PI3K/Akt
12.  A transmembrane polymorphism in FcγRIIb (FCGR2B) is associated with the production of anti-cyclic citrullinated peptide autoantibodies in Taiwanese RA 
Genes and immunity  2008;9(8):680-688.
The aim of the current study was to determine whether the FcγRIIb 187-Ile/Thr polymorphism is a predisposition factor for subtypes of RA defined by disease severity and production of autoantibodies against cyclic citrullinated peptides (anti-CCPs) in Taiwanese RA patients. Genotype distributions and allele frequencies of FcγRIIb 187-Ile/Thr were compared between 562 normal healthy controls and 640 RA patients as stratified by clinical parameters and autoantibodies. Significant enrichment of 187-Ile allele was observed in RA patients positive for anti-CCP antibodies as compared with the anti-CCP negative RA patients (P=0.001, OR 1.652 (95% CI 1.210–2.257)) or as compared with the normal controls (P =0.005, OR 1.348 (95% CI 1.092–1.664)). In addition, 187-Ile allele was found to be enriched in RA patients positive for rheumatoid factor (RF) compared to the RF negative RA patients (P=0.024, OR 1.562 (95% CI 1.059–2.303)). Furthermore, the homozygotes were enriched in destructive male RA patients (P =0.035; OR 2.038 (95% CI 1.046–3.973)) and the 187-Ile allele was associated with early-onset of RA in Taiwanese patients (P=0.045, OR 1.548 (95% CI 1.007–2.379)). Thus, FcγRIIb SNP 187-Ile/Thr may influence the RA phenotypes in Taiwanese RA.
doi:10.1038/gene.2008.56
PMCID: PMC3740516  PMID: 18633424
rheumatoid arthritis; anti-CCP antibody; FcγR; polymorphism
13.  A novel correction factor based on extended volume to complement the conformity index 
The British Journal of Radiology  2012;85(1016):e523-e529.
Objective
We propose a modified conformity index (MCI), based on extended volume, that improves on existing indices by correcting for the insensitivity of previous conformity indices to reference dose shape to assess the quality of high-precision radiation therapy and present an evaluation of its application.
Methods
In this paper, the MCI is similar to the conformity index suggested by Paddick (CIPaddick), but with a different correction factor. It is shown for three cases: with an extended target volume, with an extended reference dose volume and without an extended volume. Extended volume is generated by expanding the original volume by 0.1–1.1 cm isotropically. Focusing on the simulation model, measurements of MCI employ a sphere target and three types of reference doses: a sphere, an ellipsoid and a cube. We can constrain the potential advantage of the new index by comparing MCI with CIPaddick. The measurements of MCI in head–neck cancers treated with intensity-modulated radiation therapy and volumetric-modulated arc therapy provide a window on its clinical practice.
Results
The results of MCI for a simulation model and clinical practice are presented and the measurements are corrected for limited spatial resolution. The three types of MCI agree with each other, and comparisons between the MCI and CIPaddick are also provided.
Conclusion
The results from our analysis show that the proposed MCI can provide more objective and accurate conformity measurement for high-precision radiation therapy. In combination with a dose–volume histogram, it will be a more useful conformity index.
doi:10.1259/bjr/27949149
PMCID: PMC3587062  PMID: 22128127
14.  High molecular weight hyaluronan decreases oxidative DNA damage induced by EDTA in human corneal epithelial cells 
Ye, J | Wu, H | Wu, Y | Wang, C | Zhang, H | Shi, X | Yang, J
Eye  2012;26(7):1012-1020.
Purpose
To investigate the toxic effects of ethylenediaminetetraacetic acid disodium salt (EDTA), a corneal penetration enhancer in topical ophthalmic formulations, on DNA in human corneal epithelial cells (HCEs), and to investigate whether the effect induced by EDTA can be inhibited by high molecular weight hyaluronan (HA).
Methods
Cells were exposed to EDTA in concentrations ranging from 0.00001 to 0.01% for 60 min, or 30 min high molecular weight HA pretreatment followed by EDTA treatment. The cell viability was measured by the MTT test. Cell apoptosis was determined with annexin V staining by flow cytometry. The DNA single- and double-strand breaks of HCEs were examined by alkaline comet assay and by immunofluorescence microscope detection of the phosphorylated form of histone variant H2AX (γH2AX) foci, respectively. Reactive oxygen species (ROS) production was assessed by the fluorescent probe, 2′, 7′-dichlorodihydrofluorescein diacetate.
Results
EDTA exhibited no adverse effect on cell viability and did not induce cell apoptosis in human corneal epithelial cells at concentrations lower than 0.01%. However, a significant increase of DNA single- and double-strand breaks was observed in a dose-dependent manner with all the concentrations of EDTA tested in HCEs. In addition, EDTA treatment led to elevated ROS generation. Moreover, 30 min preincubation with high molecular weight HA significantly decreased EDTA-induced ROS generation and DNA damage.
Conclusions
EDTA could induce DNA damage in HCEs, probably through oxidative stress. Furthermore, high molecular weight HA was an effective protective agent that had antioxidant properties and decreased DNA damage induced by EDTA.
doi:10.1038/eye.2012.89
PMCID: PMC3396180  PMID: 22595911
hyaluronan; EDTA; DNA damage; ROS; corneal epithelial cell
16.  Enhancing glass-forming ability via frustration of nano-clustering in alloys with a high solvent content 
Scientific Reports  2013;3:1983.
The glass-forming ability (GFA) of alloys with a high-solvent content such as soft magnetic Fe-based and Al-based alloys is usually limited due to strong formation of the solvent-based solid solution phase. Herein, we report that the GFA of soft magnetic Fe-based alloys (with >70 at.% Fe to ensure large saturation magnetization) could be dramatically improved by doping with only 0.3 at.% Cu which has a positive enthalpy of mixing with Fe. It was found that an appropriate Cu addition could enhance the liquid phase stability and crystallization resistance by destabilizing the α-Fe nano-clusters due to the necessity to redistribute the Cu atoms. However, excessive Cu doping would stimulate nucleation of the α-Fe nano-clusters due to the repulsive nature between the Fe and Cu atoms, thus deteriorating the GFA. Our findings provide new insights into understanding of glass formation in general.
doi:10.1038/srep01983
PMCID: PMC3680804  PMID: 23760427
17.  Individually tailored screening of breast cancer with genes, tumour phenotypes, clinical attributes, and conventional risk factors 
British Journal of Cancer  2013;108(11):2241-2249.
Background:
We demonstrated how to comprehensively translate the existing and updated scientific evidence on genomic discovery, tumour phenotype, clinical features, and conventional risk factors in association with breast cancer to facilitate individually tailored screening for breast cancer.
Methods:
We proposed an individual-risk-score-based approach that translates state-of-the-art scientific evidence into the initiators and promoters affecting onset and subsequent progression of breast tumour underpinning a novel multi-variable three-state temporal natural history model. We applied such a quantitative approach to a population-based Taiwanese women periodical screening cohort.
Results:
Risk prediction for pre-clinical detectable and clinical-detected breast cancer was made by the two risk scores to stratify the underlying population to assess the optimal age to begin screening and the inter-screening interval for each category and to ascertain which high-risk group requires an alternative image technique. The risk-score-based approach significantly reduced the interval cancer rate as a percentage of the expected rate in the absence of screening by 30% and also reduced 8.2% false positive cases compared with triennial universal screening.
Conclusion:
We developed a novel quantitative approach following the principle of translational research to provide a roadmap with state-of-the-art genomic discovery and clinical parameters to facilitate individually tailored breast cancer screening.
doi:10.1038/bjc.2013.202
PMCID: PMC3681026  PMID: 23674086
translational research; individually tailored breast cancer screening; multi-state multi-variable model; breast cancer
18.  Mutation incidence and coincidence in non small-cell lung cancer: meta-analyses by ethnicity and histology (mutMap) 
Annals of Oncology  2013;24(9):2371-2376.
Background
Meta-analyses were conducted to characterize patterns of mutation incidence in non small-cell lung cancer (NSCLC).
Design
Nine genes with the most complete published mutation coincidence data were evaluated. One meta-analysis generated a ‘mutMap’ to visually represent mutation coincidence by ethnicity (Western/Asian) and histology (adenocarcinoma [ADC] or squamous cell carcinoma). Another meta-analysis evaluated incidence of individual mutations. Extended analyses explored incidence of EGFR and KRAS mutations by ethnicity, histology, and smoking status.
Results
Genes evaluated were TP53, EGFR, KRAS, LKB1, EML4-ALK, PTEN, BRAF, PIK3CA, and ErbB2. The mutMap highlighted mutation coincidences occurring in ≥5% of patients, including TP53 with KRAS or EGFR mutations in patients with ADC, and TP53 with LKB1 mutation in Western patients. TP53 was the most frequently mutated gene overall. Frequencies of TP53, EGFR, KRAS, LKB1, PTEN, and BRAF mutations were influenced by histology and/or ethnicity. Although EGFR mutations were most frequent in patients with ADC and never/light smokers from Asia, and KRAS mutations were most frequent in patients with ADC and ever/heavy smokers from Western countries, both were detected outside these subgroups.
Conclusions
Potential molecular pathology segments of NSCLC were identified. Further studies of mutations in NSCLC are warranted to facilitate more specific diagnoses and guide treatment.
doi:10.1093/annonc/mdt205
PMCID: PMC3755331  PMID: 23723294
geography; histology; lung cancer; mutation coincidence; oncogenes
19.  Glucose 6-phosphate dehydrogenase deficiency enhances germ cell apoptosis and causes defective embryogenesis in Caenorhabditis elegans 
Cell Death & Disease  2013;4(5):e616-.
Glucose 6-phosphate dehydrogenase (G6PD) deficiency, known as favism, is classically manifested by hemolytic anemia in human. More recently, it has been shown that mild G6PD deficiency moderately affects cardiac function, whereas severe G6PD deficiency leads to embryonic lethality in mice. How G6PD deficiency affects organisms has not been fully elucidated due to the lack of a suitable animal model. In this study, G6PD-deficient Caenorhabditis elegans was established by RNA interference (RNAi) knockdown to delineate the role of G6PD in animal physiology. Upon G6PD RNAi knockdown, G6PD activity was significantly hampered in C. elegans in parallel with increased oxidative stress and DNA oxidative damage. Phenotypically, G6PD-knockdown enhanced germ cell apoptosis (2-fold increase), reduced egg production (65% of mock), and hatching (10% of mock). To determine whether oxidative stress is associated with G6PD knockdown-induced reproduction defects, C. elegans was challenged with a short-term hydrogen peroxide (H2O2). The early phase egg production of both mock and G6PD-knockdown C. elegans were significantly affected by H2O2. However, H2O2-induced germ cell apoptosis was more dramatic in mock than that in G6PD-deficient C. elegans. To investigate the signaling pathways involved in defective oogenesis and embryogenesis caused by G6PD knockdown, mutants of p53 and mitogen-activated protein kinase (MAPK) pathways were examined. Despite the upregulation of CEP-1 (p53), cep-1 mutation did not affect egg production and hatching in G6PD-deficient C. elegans. Neither pmk-1 nor mek-1 mutation significantly affected egg production, whereas sek-1 mutation further decreased egg production in G6PD-deficient C. elegans. Intriguingly, loss of function of sek-1 or mek-1 dramatically rescued defective hatching (8.3- and 9.6-fold increase, respectively) induced by G6PD knockdown. Taken together, these findings show that G6PD knockdown reduces egg production and hatching in C. elegans, which are possibly associated with enhanced oxidative stress and altered MAPK pathways, respectively.
doi:10.1038/cddis.2013.132
PMCID: PMC3674345  PMID: 23640458
C. elegans; G6PD; oxidative stress; germ cell apoptosis; embryogenesis; MAPK
21.  Induction of Angiopoietin-2 after Spinal Cord Injury 
Neuroscience  2011;202:454-464.
Angiopoietin 1 (Ang-1) and angiopoietin 2 (Ang-2) have opposing effects on blood vessels, with Ang-2 being mainly induced during the endothelial barrier breakdown. It is known that spinal cord injury (SCI) induces lasting decreases in Ang-1 levels, underlying endothelial barrier disruption, but the expression of Ang-2 in spinal cord injury has not been studied. We characterized Ang-2 after SCI using a clinically relevant rat model of contusion SCI. We found that SCI induces marked and persistent upregulation of Ang-2 (up to 10 weeks after SCI), which does not reflect well-characterized temporal profile of the blood-spinal cord barrier (BSCB) breakdown after SCI, and thus suggests other role(s) for Ang-2 in injured spinal cords. Furthermore, we also found that higher Ang-2 levels were associated with more successful locomotor recovery after SCI, both in SCI rats with markedly better spontaneous motor recovery, and in SCI rats receiving a neuroprotective pharmacological intervention (amiloride), suggesting a beneficial role for Ang-2 in injured spinal cords. Immunocytochemical analyses revealed that Ang-2 was not induced in endothelial cells, but in perivascular and non-vascular cells labeled with glial fibrillary acidic protein (GFAP) or with chondroitin sulfate proteoglycan (NG2). Therefore, it is unlikely that induction of Ang-2 contributes to vascular dysfunction underlying functional impairment after SCI, but rather that it contributes to the beneficial pro-angiogenic and/or gliogenic processes underlying recovery processes after SCI.
doi:10.1016/j.neuroscience.2011.09.058
PMCID: PMC3285476  PMID: 22020092
spinal cord injury; Ang-2; Ang-1; angiogenesis; NG2; amiloride; motor recovery
22.  AMP-activated protein kinase mediates effects of oxidative stress on embryo gene expression in a mouse model of diabetic embryopathy 
Diabetologia  2011;55(1):245-254.
Aims/hypothesis
Neural tube defects (NTDs) are a common malformation associated with diabetic embryopathy. Maternal hyperglycaemia-induced oxidative stress inhibits the expression of Pax3, a gene that is essential for neural tube closure, and increases the incidence of NTDs. Because oxidative stress can stimulate AMP-activated kinase (AMPK) activity, and AMPK can regulate gene transcription, we hypothesised that increased AMPK activity would mediate the adverse effects of maternal hyperglycaemia-induced oxidative stress on Pax3 expression and NTDs.
Methods
Pregnant mice were made transiently hyperglycaemic by glucose injection, or hypoxic by housing in a hypoxic chamber, or were treated with antimycin A to induce oxidative stress, and AMPK activity in the embryos was assayed. The effects of stimulating AMPK activity with 5-aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside (AICAR) on Pax3 expression and NTDs were determined. Vitamin E or glutathione ethyl ester was used to reduce oxidative stress, and compound C was used to inhibit AMPK activation. Murine embryonic stem cells were employed as an in vitro model to study the effects of oxidative stress on AMPK activity and the effects of AMPK stimulation on Pax3 expression.
Results
Maternal hyperglycaemia stimulated AMPK activity, and stimulation of AMPK with AICAR inhibited Pax3 expression (in vivo and in vitro) and increased NTDs (in vivo). Stimulation of AMPK by hyperglycaemia, hypoxia or antimycin A was inhibited by antioxidants. The AMPK inhibitor compound C blocked the effects of hyperglycaemia or AA on Pax3 expression and NTDs.
Conclusions/interpretation
Stimulation of AMPK in embryos during a diabetic pregnancy mediates the effects of hyperglycaemia-induced oxidative stress to disturb the expression of the critical Pax3 gene, thereby causing NTDs.
doi:10.1007/s00125-011-2326-y
PMCID: PMC3342033  PMID: 21993711
AMP-activated kinase; Diabetic embryopathy; Diabetic pregnancy; Neural tube defect; Pax3; Oxidative stress
23.  The contribution of antenatal care to the coverage and correlates of HIV testing among adults in Zimbabwe 2005–06 
Summary
Expanding the availability, utilization and coverage of HIV testing services is a critical step towards primary prevention and successful delivery of antiretroviral therapy (ART) in Zimbabwe. We used data from the Zimbabwe Demographic and Health Survey (2005–2006) to examine the coverage and correlates of recent HIV testing (HIV testing, <24 months preceding the survey) among HIV-positive and HIV-negative adults. We estimated the relative contribution of HIV testing in both the antenatal care (ANC) setting and non-ANC settings. Uptake of recent HIV testing was 14.4% among women and 11.1% among men, with HIV testing in ANC accounting for 42.3% and 10.3% of all recent testing among women and men, respectively. In the multivariate analyses, recent pregnancies and being aware of ART were independent correlates after controlling for demographic and socioeconomic variables. HIV testing in ANC was an important contributor to HIV testing coverage in Zimbabwe by reaching not only pregnant women but also their partners.
doi:10.1258/ijsa.2011.011274
PMCID: PMC3422888  PMID: 22648882
HIV testing; adult; screening; antenatal care; coverage; PMTCT; Zimbabwe; Africa
24.  Polypeptide N-acetylgalactosaminyltransferase 6 expression in pancreatic cancer is an independent prognostic factor indicating better overall survival 
British Journal of Cancer  2011;104(12):1882-1889.
Background:
The family of polypeptide N-acetylgalactosaminyltransferases (GalNAc-Ts) is responsible for the altered glycosylation in cancer. The purpose of our study was to investigate the clinical significance of two isoforms, GalNAc-T6 and -T3, and their correlation with the prognosis of pancreatic cancer.
Methods:
Immunohistochemistry was used to analyse GalNAc-T6 and -T3 expressions in 70 clinicopathologically characterised pancreatic cancer cases.
Results:
Positive expressions of GalNAc-T6 and -T3 were immunohistochemically identified in 51% (36 of 70) and in 77% (54 of 70) of patients, respectively. A close relationship was noted between GalNAc-T6 positive expression and pathological well/moderate differentiated type (P=0.001), small tumour size (P=0.044), absence of vascular invasion (P=0.009), and low stage of the American Joint Committee on Cancer systems (P=0.043). The expression of GalNAc-T3 significantly correlated with good differentiation (P=0.001), but not with other clinicopathologic features. Furthermore, univariate and multivariate analyses revealed that GalNAc-T6 expression was an independent prognosis indicator for the disease, whereas GalNAc-T3 expression had no impact on clinical outcome, even though 33 of 36 GalNAc-T6-positive cases also had a positive expression of GalNAc-T3 (P=0.001, r=0.356).
Conclusion:
Both GalNAc-T6 and -T3 expressions correlated significantly with tumour differentiation, whereas only GalNAc-T6 expression predicted prognosis in pancreatic cancer.
doi:10.1038/bjc.2011.166
PMCID: PMC3111199  PMID: 21587259
pancreatic cancer; GalNAc-T6; GalNAc-T3; prognosis; metastasis
25.  Cluster-tic syndrome as the initial manifestation of multiple sclerosis 
The Journal of Headache and Pain  2012;13(5):425-429.
We report the case of a patient diagnosed as having cluster-tic syndrome as the initial manifestation of multiple sclerosis (MS). The patient’s headache bouts improved after treatment with antiepileptic drugs, steroids, and beta-interferon. Magnetic resonance imaging (MRI) scans showed a pontine demyelinating lesion involving the area of the trigeminal root inlet and main sensory nucleus. Neurophysiological studies correlated well with MRI lesions. The association between cluster-tic syndrome and MS is an exception, and the mechanism of the pain is still unknown; therefore, this case might suggest a pathophysiological relationship between the trigeminal main sensory nucleus and cluster-tic syndrome.
doi:10.1007/s10194-012-0449-2
PMCID: PMC3381064  PMID: 22543446

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