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1.  Chronic physical health conditions among children of different racial/ethnic backgrounds 
Public health  2013;127(6):546-553.
Objectives
It is estimated that 20% of children in the USA are affected by at least one chronic disease. Although the burden of chronic conditions is greater for minority populations of children, research that has explored the prevalence and risk factors of chronic disease across different racial/ethnic groups is scarce. The aim of this study was to examine racial/ethnic disparities in the prevalence rates of common physical, chronic diseases in White, Black and Hispanic children; and assess the effect of several factors on the risk of having a chronic disease.
Methods
Using the 2007 National Survey of Childrens Health, prevalence estimates were calculated for asthma, hearing impairment, visual impairment, joint/bone/muscle problems, brain injury and other illnesses for each racial/ethnic group. Multivariate logistic regression analyses were conducted to examine the effects of several risk factors on the risk of each of these health conditions.
Results
The findings show that the prevalence for all health conditions was significantly higher (25.3%) among Black children than White (19.8%) and Hispanic (18.6%) children. Furthermore, 19.5% of Black children have had or currently have asthma compared with 12.2% of White and Hispanic children. More Black and Hispanic children were covered by public health insurance, while 19% of Hispanic children were currently uninsured. White children whose mothers had a health problem were associated with asthma, hearing impairment, visual impairment and joint/bone/muscle problems, while Black children were more likely to report asthma and Hispanics reported visual impairment and joint/ bone muscle problems. Hispanic children who were living in poverty or were uninsured were at lower risk for any chronic disease. Regardless of race/ethnicity, children living in a single-parent household were more likely to be associated with any health condition.\
Conclusions
This study provides evidence that racial/ethnic disparities in chronic physical conditions and health care among US children are extensive. It underscores that uninsured children who do not have access to the healthcare system are not being screened for chronic diseases, or are not obtaining medical care for such health problems. Healthcare providers should educate families about prevention measures and community services that might be able to assist them in improving the health of their children.
doi:10.1016/j.puhe.2013.02.006
PMCID: PMC4086459  PMID: 23583033
Chronic; Physical health illnesses; Children; Race and ethnicity; Asthma; Hearing and vision; Health disparities
2.  Synergistic interaction of benign prostatic hyperplasia and prostatitis on prostate cancer risk 
British Journal of Cancer  2013;108(9):1778-1783.
Background:
The incidence of prostate cancer is much lower in Asian men than in Western men. This study investigated whether prostate cancer is associated with prostatitis, benign prostatic hyperplasia (BPH), and other medical conditions in the low-incidence population.
Methods:
From the claims data obtained from the universal National Health Insurance of Taiwan, we identified 1184 patients with prostate cancer diagnosed from 1997 to 2008. Controls comprised 4736 men randomly selected from a cancer-free population. Both groups were 50 years of age or above. Medical histories between the two groups were compared.
Results:
Multivariate logistic regression analysis showed that prostatitis and BPH had stronger association with prostate cancer than the other medical conditions tested. Compared with men without prostatitis and BPH, a higher odds ratio (OR) for prostate cancer was associated with BPH (26.2, 95% confidence interval (CI) 20.8–33.0) than with prostatitis (10.5, 95% CI=3.36–32.7). Men with both conditions had an OR of 49.2 (95% CI=34.7–69.9).
Conclusion:
Men with prostate cancer have strong association with prostatitis and/or BPH. Prostatitis interacts with BPH, resulting in higher estimated relative risk of prostate cancer in men suffering from both conditions.
doi:10.1038/bjc.2013.184
PMCID: PMC3658521  PMID: 23612451
benign prostatic hyperplasia; prostatitis; diabetes; interaction; prostate cancer
3.  Expression of Immediate-Early Genes in the Inferior Colliculus and Auditory Cortex in Salicylate-Induced Tinnitus in Rat 
Tinnitus could be associated with neuronal hyperactivity in the auditory center. As a neuronal activity marker, immediate-early gene (IEG) expression is considered part of a general neuronal response to natural stimuli. Some IEGs, especially the activity-dependent cytoskeletal protein (Arc) and the early growth response gene-1 (Egr-1), appear to be highly correlated with sensory-evoked neuronal activity. We hypothesize, therefore, an increase of Arc and Egr-1 will be observed in a tinnitus model. In our study, we used the gap prepulse inhibition of acoustic startle (GPIAS) paradigm to confirm that salicylate induces tinnitus-like behavior in rats. However, expression of the Arc gene and Egr-1 gene were decreased in the inferior colliculus (IC) and auditory cortex (AC), in contradiction of our hypothesis. Expression of N-methyl D-aspartate receptor subunit 2B (NR2B) was increased and all of these changes returned to normal 14 days after treatment with salicylate ceased. These data revealed long-time administration of salicylate induced tinnitus markedly but reversibly and caused neural plasticity changes in the IC and the AC. Decreased expression of Arc and Egr-1 might be involved with instability of synaptic plasticity in tinnitus.
doi:10.4081/ejh.2014.2294
PMCID: PMC3980210  PMID: 24704997
salicylate; inferior colliculus; auditory cortex; activity-dependent cytoskeletal protein; early growth response gene-1
4.  Botulinum toxin injections combined with or without sodium hyaluronate in the absence of electromyography for the treatment of infantile esotropia: a pilot study 
Chen, J | Deng, D | Zhong, H | Lin, X | Kang, Y | Wu, H | Yan, J | Mai, G
Eye  2012;27(3):382-386.
Objective
To evaluate the feasibility and safety of a revised technique of botulinum toxin type A (BTA) injections for the treatment of infantile esotropia.
Methods
Forty-seven patients with infantile esotropia were randomly divided into two groups. In group A, 23 cases were treated with a bilateral injection of 2.5–3.75 U BTA combined with sodium hyaluronate (SH) to the medial rectus muscle. In group B, 24 cases were treated with a bilateral injection of 2.5–3.75 U BTA solution alone to the medial rectus muscle. Electromyography was not used in the study. All patients received one injection and were evaluated 2 weeks, 3 months, and 6 months following injection.
Results
The measured changes between groups A and B included the frequencies of good alignment 6 months after injections (30.4% vs 37.5%), complicated ptosis (2.2% vs 20.8%), and vertical deviation (2.2% vs 2.1%).
Conclusion
BTA injections combined with or without SH in the absence of electromyography demonstrated effectiveness and feasibility in the treatment of infantile esotropia. A relative decrease in the frequency of complicated ptosis resulted from injections of BTA+SH.
doi:10.1038/eye.2012.264
PMCID: PMC3597871  PMID: 23238444
botulinum toxin; infantile esotropia; sodium hyaluronate; complication
5.  CD123 targeting oncolytic adenoviruses suppress acute myeloid leukemia cell proliferation in vitro and in vivo 
Li, G | Li, X | Wu, H | Yang, X | Zhang, Y | Chen, L | Wu, X | Cui, L | Wu, L | Luo, J | Liu, X Y
Blood Cancer Journal  2014;4(3):e194-.
We report here a novel strategy to redirect oncolytic adenoviruses to CD123 by carry a soluble coxsackie-adenovirus receptor (sCAR)-IL3 expression cassette in the viral genome to form Ad.IL3, which sustainably infected acute myeloid leukemia (AML) cells through CD123. Ad.IL3 was further engineered to harbor gene encoding manganese superoxide dismutase (MnSOD) or mannose-binding plant lectin Pinellia pedatisecta agglutinin (PPA), forming Ad.IL3-MnSOD and Ad.IL3-PPA. As compared with Ad.IL3 or Ad.sp-E1A control, Ad.IL3-MnSOD and Ad.IL3-PPA significantly suppressed in vitro proliferation of HL60 and KG-1 cells. Elevated apoptosis was detected in HL60 and KG-1 cells treated with either Ad.IL3-MnSOD or Ad.IL3-PPA. The caspase-9–caspase-7 pathway was determined to be activated by Ad.IL3-MnSOD as well as by Ad.IL3-PPA in HL60 cells. In an HL60/Luc xenograft nonobese diabetic/severe-combined immunodeficiency mice model, Ad.IL3-MnSOD and Ad.IL3-PPA suppressed cancer cell growth as compared with Ad.IL3. A significant difference of cancer cell burden was detected between Ad.IL3 and Ad.IL3-PPA groups at day 9 after treatment. Furthermore, Ad.IL3-MnSOD significantly prolonged mouse survival as compared with Ad.sp-E1A. These findings demonstrated that Ad.IL3-gene could serve as a novel agent for AML therapy. Harboring sCAR-ligand expression cassette in the viral genome may provide a universal method to redirect oncolytic adenoviruses to various membrane receptors on cancer cells resisting serotype 5 adenovirus infection.
doi:10.1038/bcj.2014.15
PMCID: PMC3972701  PMID: 24658372
6.  Two-Dimensional Tomography from Noisy Projections Taken at Unknown Random Directions* 
SIAM journal on imaging sciences  2013;6(1):136-175.
Computerized tomography is a standard method for obtaining internal structure of objects from their projection images. While CT reconstruction requires the knowledge of the imaging directions, there are some situations in which the imaging directions are unknown, for example, when imaging a moving object. It is therefore desirable to design a reconstruction method from projection images taken at unknown directions. Another difficulty arises from the fact that the projections are often contaminated by noise, practically limiting all current methods, including the recently proposed diffusion map approach. In this paper, we introduce two denoising steps that allow reconstructions at much lower signal-to-noise ratios (SNRs) when combined with the diffusion map framework. In the first denoising step we use principal component analysis (PCA) together with classical Wiener filtering to derive an asymptotically optimal linear filter. In the second step, we denoise the graph of similarities between the filtered projections using a network analysis measure such as the Jaccard index. Using this combination of PCA, Wiener filtering, graph denoising, and diffusion maps, we are able to reconstruct the two-dimensional (2-D) Shepp–Logan phantom from simulative noisy projections at SNRs well below their currently reported threshold values. We also report the results of a numerical experiment corresponding to an abdominal CT. Although the focus of this paper is the 2-D CT reconstruction problem, we believe that the combination of PCA, Wiener filtering, graph denoising, and diffusion maps is potentially useful in other signal processing and image analysis applications.
doi:10.1137/090764657
PMCID: PMC3929313  PMID: 24563691
computerized tomography; diffusion maps; graph denoising; principal component analysis; Wiener filtering; Jaccard index; small world graph; Shepp–Logan phantom
7.  PAINFUL NERVE INJURY DECREASES SARCO-ENDOPLASMIC RETICULUM CA2+-ATPASE ACTIVITY IN AXOTOMIZED SENSORY NEURONS 
Neuroscience  2012;231:247-257.
The sarco-endoplasmic reticulum Ca2+-ATPase (SERCA) is a critical pathway by which sensory neurons sequester cytosolic Ca2+ and thereby maintain intracellular Ca2+ homeostasis. We have previously demonstrated decreased intraluminal endoplasmic reticulum Ca2+ concentration in traumatized sensory neurons. Here we examine SERCA function in dissociated sensory neurons using Fura-2 fluorometry. Blocking SERCA with thapsigargin (1 μM) increased resting [Ca2+]c and prolonged recovery (τ) from transients induced by neuronal activation (elevated bath K+), demonstrating SERCA contributes to control of resting [Ca2+]c and recovery from transient [Ca2+]c elevation. To evaluate SERCA in isolation, plasma membrane Ca2+ ATPase was blocked with pH 8.8 bath solution and mitochondrial buffering was avoided by keeping transients small (≤400 nM). Neurons axotomized by spinal nerve ligation (SNL) showed a slowed rate of transient recovery compared to control neurons, representing diminished SERCA function, whereas neighboring non-axotomized neurons from SNL animals were unaffected. Injury did not affect SERCA function in large neurons. Repeated depolarization prolonged transient recovery, showing that neuronal activation inhibits SERCA function. These findings suggest that injury-induced loss of SERCA function in small sensory neurons may contribute to the generation of pain following peripheral nerve injury.
doi:10.1016/j.neuroscience.2012.11.055
PMCID: PMC3715030  PMID: 23219911
sarco-endoplasmic reticulum Ca2+-ATPase; Ca2+ homeostasis; neuropathic pain; endoplasmic reticulum; sensory neuron
8.  CYP2D6 Genotype and Adjuvant Tamoxifen: Meta-Analysis of Heterogeneous Study Populations 
The International Tamoxifen Pharmacogenomics Consortium was established to address the controversy regarding cytochrome P450 2D6 (CYP2D6) status and clinical outcomes in tamoxifen therapy. We performed a meta-analysis on data from 4,973 tamoxifen-treated patients (12 globally distributed sites). Using strict eligibility requirements (postmenopausal women with estrogen receptor–positive breast cancer, receiving 20 mg/day tamoxifen for 5 years, criterion 1); CYP2D6 poor metabolizer status was associated with poorer invasive disease–free survival (IDFS: hazard ratio = 1.25; 95% confidence interval = 1.06, 1.47; P = 0.009). However, CYP2D6 status was not statistically significant when tamoxifen duration, menopausal status, and annual follow-up were not specified (criterion 2, n = 2,443; P = 0.25) or when no exclusions were applied (criterion 3, n = 4,935; P = 0.38). Although CYP2D6 is a strong predictor of IDFS using strict inclusion criteria, because the results are not robust to inclusion criteria (these were not defined a priori), prospective studies are necessary to fully establish the value of CYP2D6 genotyping in tamoxifen therapy.
doi:10.1038/clpt.2013.186
PMCID: PMC3904554  PMID: 24060820
9.  Vector Diffusion Maps and the Connection Laplacian 
Communications on pure and applied mathematics  2012;65(8):10.1002/cpa.21395.
We introduce vector diffusion maps (VDM), a new mathematical framework for organizing and analyzing massive high-dimensional data sets, images, and shapes. VDM is a mathematical and algorithmic generalization of diffusion maps and other nonlinear dimensionality reduction methods, such as LLE, ISOMAP, and Laplacian eigenmaps. While existing methods are either directly or indirectly related to the heat kernel for functions over the data, VDM is based on the heat kernel for vector fields. VDM provides tools for organizing complex data sets, embedding them in a low-dimensional space, and interpolating and regressing vector fields over the data. In particular, it equips the data with a metric, which we refer to as the vector diffusion distance. In the manifold learning setup, where the data set is distributed on a low-dimensional manifold ℳd embedded in ℝp, we prove the relation between VDM and the connection Laplacian operator for vector fields over the manifold.
doi:10.1002/cpa.21395
PMCID: PMC3886882  PMID: 24415793
11.  DNA damage-induced sustained p53 activation contributes to inflammation-associated hepatocarcinogenesis in rats 
Oncogene  2012;32(38):10.1038/onc.2012.451.
The tumor suppressor p53 has an important role in inducing cell-intrinsic responses to DNA damage, including cellular senescence or apoptosis, which act to thwart tumor development. It has been shown, however, that senescent or dying cells are capable of eliciting inflammatory responses, which can have pro-tumorigenic effects. Whether DNA damage-induced p53 activity can contribute to senescence- or apoptosis-associated pro-tumorigenic inflammation is unknown. Recently, we generated a p53 knock-out rat via homologous recombination in rat embryonic stem cells. Here we show that in a rat model of inflammation-associated hepatocarcinogenesis, heterozygous deficiency of p53 resulted in attenuated inflammatory responses and ameliorated hepatic cirrhosis and tumorigenesis. Chronic administration of hepatocarcinogenic compound, diethylnitrosamine, led to persistent DNA damage and sustained induction of p53 protein in the wild-type livers, and much less induction in p53 heterozygous livers. Sustained p53 activation subsequent to DNA damage was accompanied by apoptotic rather than senescent hepatic injury, which gave rise to the hepatic inflammatory responses. In contrast, the non-hepatocarcinogenic agent, carbon tetrachloride, failed to induce p53, and caused a similar degree of chronic hepatic inflammation and cirrhosis in wild type and p53 heterozygous rats. These results suggest that although p53 is usually regarded as a tumor suppressor, its constant activation can promote pro-tumorigenic inflammation, especially in livers exposed to agents that inflict lasting mutagenic DNA damage.
doi:10.1038/onc.2012.451
PMCID: PMC3855850  PMID: 23069657
DNA damage; p53; inflammation; cirrhosis; hepatocellular carcinoma
12.  Ghrelin receptor regulates HFCS-induced adipose inflammation and insulin resistance 
Nutrition & Diabetes  2013;3(12):e99-.
Background and Objectives:
High fructose corn syrup (HFCS) is the most commonly used sweetener in the United States. Some studies show that HFCS consumption correlates with obesity and insulin resistance, while other studies are in disagreement. Owing to conflicting and insufficient scientific evidence, the safety of HFCS consumption remains controversial.
Subjects/Methods:
We investigated the metabolic consequences of mice fed a (a) regular diet, (b) ‘Western' high-fat diet or (c) regular diet supplemented with 8% HFCS in drinking water (to mimic soft drinks) for 10 months. Adipose tissue macrophages (ATMs) have emerged as a major pathogenic factor for obesity and insulin resistance. ATMs consist of proinflammatory F4/80+CD11c+ macrophages and anti-inflammatory F4/80+CD11c− macrophages. In this study, we assessed the effects of HFCS on ATMs in intra-abdominal fat.
Results:
We found that HFCS feeding in mice induced more severe adipose inflammation and insulin resistance than even the higher-calorie-containing ‘Western' high-fat diet, and these HFCS-induced deleterious effects were independent of calorie intake or body fat content. We showed that similar to ‘Western' high-fat diet, HFCS triggered a robust increase of both proinflammatory ATMs and anti-inflammatory ATMs in intra-abdominal fat. Remarkably, however, the anti-inflammatory ATMs were much less abundant in HFCS-fed mice than in high-fat-fed mice. Furthermore, we showed that deletion of the ghrelin receptor (growth hormone secretagogue receptor, GHS-R) ameliorates HFCS-induced adipose inflammation and insulin resistance. HFCS-fed GHS-R-null mice exhibit decreased proinflammatory ATMs in intra-abdominal fat, reduced adipose inflammation and attenuated liver steatosis.
Conclusion:
Our studies demonstrate that HFCS has detrimental effects on metabolism, suggesting that dietary guidelines on HFCS consumption for Americans may need to be revisited. GHS-R deletion mitigates the effects of HFCS on adipose inflammation and insulin resistance, suggesting that GHS-R antagonists may represent a novel therapy for insulin resistance.
doi:10.1038/nutd.2013.41
PMCID: PMC3877431  PMID: 24366371
ghrelin receptor; HFCS; macrophages; inflammation; insulin resistance; liver steatosis
13.  Effects of Graded Levels of Montmorillonite on Performance, Hematological Parameters and Bone Mineralization in Weaned Pigs 
The aim of this study was to investigate the effects of graded levels of montmorillonite, a constituent of clay, on performance, hematological parameters and bone mineralization in weaned pigs. One hundred and twenty, 35-d-old crossbred pigs (Duroc×Large White×Landrace, 10.50±1.20 kg) were used in a 28-d experiment and fed either an unsupplemented corn-soybean meal basal diet or similar diets supplemented with 0.5, 1.0, 2.5 or 5.0% montmorillonite added at the expense of wheat bran. Each treatment was replicated six times with four pigs (two barrows and two gilts) per replicate. Feed intake declined (linear and quadratic effect, p< 0.01) with increasing level of montmorillonite while feed conversion was improved (linear and quadratic effect, p<0.01). Daily gain was unaffected by dietary treatment. Plasma myeloperoxidase declined linearly (p = 0.03) with increasing dietary level of montmorillonite. Plasma malondialdehyde and nitric oxide levels were quadratically affected (p<0.01) by montmorillonite with increases observed for pigs fed the 0.5 and 1.0% levels which then declined for pigs fed the 2.5 and 5.0% treatments. In bone, the content of potassium, sodium, copper, iron, manganese and magnesium were decreased (linear and quadratic effect, p<0.01) in response to an increase of dietary montmorillonite. These results suggest that dietary inclusion of montmorillonite at levels as high as 5.0% does not result in overt toxicity but could induce potential oxidative damage and reduce bone mineralization in pigs.
doi:10.5713/ajas.2012.12698
PMCID: PMC4093821  PMID: 25049749
Montmorillonite; Growth Performance; Hematological Parameters; Bone Mineralization; Weaned Pig
14.  Restoration of distorted colour microscopic images from transverse chromatic aberration of imperfect lenses 
Journal of microscopy  2010;241(2):10.1111/j.1365-2818.2010.03443.x.
Summary
An algorithm is presented for restoration of colour microscopic images with distortions from imperfect microscope lenses having transverse chromatic aberrations, resulting in a magnification that slightly varies with wavelengths or colours. The differential of each colour component image is computed as the difference between the component image and its slightly magnified version. The absolute values in the differential component images are generally higher at the edges where greater discontinuities occur. The two cross-correlation functions of the absolute differentials between red and green colours and between red and blue colours are then computed. The maximum in the two cross-correlation functions were sought, respectively, and the cross-correlation delays were then calculated. The two cross-correlation delays were used to determine dispersions and to realign the three colour components. Results of real microscopic images are provided. The restored image and the original are compared both visually and quantitatively in terms of the estimated entropies measured for the degree of concentrations using vector distributions.
doi:10.1111/j.1365-2818.2010.03443.x
PMCID: PMC3807600  PMID: 21902693
Image restoration; microscopy imaging; microscope lens; transverse chromatic aberration
15.  Hepatitis B virus subgenotype C2- and B2-associated mutation patterns may be responsible for liver cirrhosis and hepatocellular carcinoma, respectively 
The objective of this study was to examine hepatitis B virus (HBV) subgenotypes and mutations in enhancer II, basal core promoter, and precore regions of HBV in relation to risks of liver cirrhosis (LC) and hepatocellular carcinoma (HCC) in Southeast China. A case-control study was performed, including chronic hepatitis B (CHB; n=125), LC (n=120), and HCC (n=136). HBV was genotyped by multiplex polymerase chain reaction and subgenotyped by restriction fragment length polymorphism. HBV mutations were measured by DNA sequencing. HBV genotype C (68.2%) predominated and genotype B (30.2%) was the second most common. Of these, C2 (67.5%) was the most prevalent subgenotype, and B2 (30.2%) ranked second. Thirteen mutations with a frequency >5% were detected. Seven mutation patterns (C1653T, G1719T, G1730C, T1753C, A1762T, G1764A, and G1799C) were associated with C2, and four patterns (C1810T, A1846T, G1862T, and G1896A) were associated with B2. Six patterns (C1653T, G1730C, T1753C, A1762T, G1764A, and G1799C) were obviously associated with LC, and 10 patterns (C1653T, G1730C, T1753C, A1762T, G1764A, G1799C, C1810T, A1846T, G1862T, and G1896A) were significantly associated with HCC compared with CHB. Four patterns (C1810T, A1846T, G1862T, and G1896A) were significantly associated with HCC compared with LC. Multivariate regression analyses showed that HBV subgenotype C2 and C2-associated mutation patterns (C1653T, T1753C, A1762T, and G1764A) were independent risk factors for LC when CHB was the control, and that B2-associated mutation patterns (C1810T, A1846T, G1862T, and G1896A) were independent risk factors for HCC when LC was the control.
doi:10.1590/1414-431X20133032
PMCID: PMC3859330  PMID: 23903686
Hepatitis B virus; Genotype; Core promoter; Precore; Mutation; Advanced liver disease
16.  Electronic superlattice revealed by resonant scattering from random impurities in Sr3Ru2O7 
Scientific Reports  2013;3:2299.
Resonant elastic x-ray scattering (REXS) is an exquisite element-sensitive tool for the study of subtle charge, orbital, and spin superlattice orders driven by the valence electrons, which therefore escape detection in conventional x-ray diffraction (XRD). Although the power of REXS has been demonstrated by numerous studies of complex oxides performed in the soft x-ray regime, the cross section and photon wavelength of the material-specific elemental absorption edges ultimately set the limit to the smallest superlattice amplitude and periodicity one can probe. Here we show – with simulations and REXS on Mn-substituted Sr3Ru2O7 – that these limitations can be overcome by performing resonant scattering experiments at the absorption edge of a suitably-chosen, dilute impurity. This establishes that – in analogy with impurity-based methods used in electron-spin-resonance, nuclear-magnetic resonance, and Mössbauer spectroscopy – randomly distributed impurities can serve as a non-invasive, but now momentum-dependent probe, greatly extending the applicability of resonant x-ray scattering techniques.
doi:10.1038/srep02299
PMCID: PMC3730170  PMID: 23903555
17.  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
18.  Interaction of Sirt3 with OGG1 contributes to repair of mitochondrial DNA and protects from apoptotic cell death under oxidative stress 
Cell Death & Disease  2013;4(7):e731-.
Sirtuin 3 (Sirt3), a major mitochondrial NAD+-dependent deacetylase, targets various mitochondrial proteins for lysine deacetylation and regulates important cellular functions such as energy metabolism, aging, and stress response. In this study, we identified the human 8-oxoguanine-DNA glycosylase 1 (OGG1), a DNA repair enzyme that excises 7,8-dihydro-8-oxoguanine (8-oxoG) from damaged genome, as a new target protein for Sirt3. We found that Sirt3 physically associated with OGG1 and deacetylated this DNA glycosylase and that deacetylation by Sirt3 prevented the degradation of the OGG1 protein and controlled its incision activity. We further showed that regulation of the acetylation and turnover of OGG1 by Sirt3 played a critical role in repairing mitochondrial DNA (mtDNA) damage, protecting mitochondrial integrity, and preventing apoptotic cell death under oxidative stress. We observed that following ionizing radiation, human tumor cells with silencing of Sirt3 expression exhibited deteriorated oxidative damage of mtDNA, as measured by the accumulation of 8-oxoG and 4977 common deletion, and showed more severe mitochondrial dysfunction and underwent greater apoptosis in comparison with the cells without silencing of Sirt3 expression. The results reported here not only reveal a new function and mechanism for Sirt3 in defending the mitochondrial genome against oxidative damage and protecting from the genotoxic stress-induced apoptotic cell death but also provide evidence supporting a new mtDNA repair pathway.
doi:10.1038/cddis.2013.254
PMCID: PMC3730425  PMID: 23868064
Sirt3; OGG1; mitochondria; DNA repair; apoptosis
20.  Prediction of microvascular invasion of hepatocellular carcinoma by pre-operative CT imaging 
The British Journal of Radiology  2012;85(1014):778-783.
Objective
The aim of this study was to diagnose microvascular invasion in patients with solitary hepatocellular carcinoma (HCC) from pre-operative CT imaging.
Methods
102 patients with solitary HCC who underwent curative hepatectomy were retrospectively included in our study. The pre-operative 3-phase CT imaging and laboratory data for the 102 patients were reviewed. Tumour size, tumour margin, peritumoral enhancement and α-fetoprotein level were assessed. Surgical pathology was reviewed; tumour differentiation, liver fibrosis score and microvascular invasion were recorded.
Results
The histopathological results revealed that 50 HCCs were positive and the other 52 were negative for microvascular invasion. Univariate analysis revealed that tumour size (p=0.036), higher Edmondson–Steiner grade (p=0.047) and non-smooth tumour margin (p<0.001) showed statistically significant associations with microvascular invasion. Multivariate logistic regression analysis showed that non-smooth tumour margin had a statistically significant association with microvascular invasion only (p<0.001). The sensitivity, specificity, positive predictive value and negative predictive value of the non-smooth tumour margin in the prediction of microvascular invasion were 66%, 86.5%, 82.5% and 72.6%, respectively.
Conclusion
Non-smooth tumour margin in pre-operative CT had a statistically significant association with microvascular invasion. More aggressive treatment should be considered in HCC patients with suspected positive microvascular invasion.
doi:10.1259/bjr/65897774
PMCID: PMC3474124  PMID: 21828149
21.  Exposure to bisphenol A disrupts meiotic progression during spermatogenesis in adult rats through estrogen-like activity 
Liu, C | Duan, W | Li, R | Xu, S | Zhang, L | Chen, C | He, M | Lu, Y | Wu, H | Pi, H | Luo, X | Zhang, Y | Zhong, M | Yu, Z | Zhou, Z
Cell Death & Disease  2013;4(6):e676-.
The effect of bisphenol A (BPA) on the reproductive system is highly debated but has been associated with meiotic abnormalities. However, evidence is lacking with regard to the mechanisms involved. In order to explore the underlying mechanisms of BPA-induced meiotic abnormalities in adult male rats, we exposed 9-week-old male Wistar rats to BPA by gavage at 0, 2, 20 or 200 μg/kg body weight (bw)/day for 60 consecutive days. 17β-Estradiol (E2) was administered at 10 μg/kg bw/day as the estrogenic positive control. Treatments with 200 μg/kg bw/day of BPA and E2 significantly decreased sperm counts and inhibited spermiation, characterized by an increase in stage VII and decrease in stage VIII in the seminiferous epithelium. This was concomitant with a disruption in the progression of meiosis I and the persistence of meiotic DNA strand breaks in pachytene spermatocytes,and the ataxia–telangiectasia-mutated and checkpoint kinase 2 signal pathway was also activated; Eventually, germ cell apoptosis was triggered as evaluated by terminal dUTP nick-end labeling assay and western blot for caspase 3. Using the estrogen receptor (ER) antagonist ICI 182780, we determined that ER signaling mediated BPA-induced meiotic disruption and reproductive impairment. Our results suggest that ER signaling-mediated meiotic disruption may be a major contributor to the molecular events leading to BPA-related male reproductive disorders. These rodent data support the growing association between BPA exposure and the rapid increase in the incidence of male reproductive disorders.
doi:10.1038/cddis.2013.203
PMCID: PMC3702305  PMID: 23788033
bisphenol A; meiocyte spreading; meiosis; spermatogenesis; stage of seminiferous epithelium
22.  Phosphorylation of HtrA2 by cyclin-dependent kinase-5 is important for mitochondrial function 
Cell Death and Differentiation  2011;19(2):257-266.
The role of the serine protease HtrA2 in neuroprotection was initially identified by the demonstration of neurodegeneration in mice lacking HtrA2 expression or function, and the interesting finding that mutations adjacent to two putative phosphorylation sites (S142 and S400) have been found in Parkinson's disease patients. However, the mechanism of this neuroprotection and the signalling pathways associated with it remain mostly unknown. Here we report that cyclin-dependent kinase-5 (Cdk5), a kinase implicated in the pathogenesis of several neurodegenerative diseases, is responsible for phosphorylating HtrA2 at S400. HtrA2 and Cdk5 interact in human and mouse cell lines and brain, and Cdk5 phosphorylates S400 on HtrA2 in a p38-dependent manner. Phosphorylation of HtrA2 at S400 is involved in maintaining mitochondrial membrane potential under stress conditions and is important for mitochondrial function, conferring cells protection against cellular stress.
doi:10.1038/cdd.2011.90
PMCID: PMC3191116  PMID: 21701498
HtrA2; Cdk5; phosphorylation; mitochondria; Parkinson's disease
23.  Exome sequencing-driven discovery of coding polymorphisms associated with common metabolic phenotypes 
Albrechtsen, A. | Grarup, N. | Li, Y. | Sparsø, T. | Tian, G. | Cao, H. | Jiang, T. | Kim, S. Y. | Korneliussen, T. | Li, Q. | Nie, C. | Wu, R. | Skotte, L. | Morris, A. P. | Ladenvall, C. | Cauchi, S. | Stančáková, A. | Andersen, G. | Astrup, A. | Banasik, K. | Bennett, A. J. | Bolund, L. | Charpentier, G. | Chen, Y. | Dekker, J. M. | Doney, A. S. F. | Dorkhan, M. | Forsen, T. | Frayling, T. M. | Groves, C. J. | Gui, Y. | Hallmans, G. | Hattersley, A. T. | He, K. | Hitman, G. A. | Holmkvist, J. | Huang, S. | Jiang, H. | Jin, X. | Justesen, J. M. | Kristiansen, K. | Kuusisto, J. | Lajer, M. | Lantieri, O. | Li, W. | Liang, H. | Liao, Q. | Liu, X. | Ma, T. | Ma, X. | Manijak, M. P. | Marre, M. | Mokrosiński, J. | Morris, A. D. | Mu, B. | Nielsen, A. A. | Nijpels, G. | Nilsson, P. | Palmer, C. N. A. | Rayner, N. W. | Renström, F. | Ribel-Madsen, R. | Robertson, N. | Rolandsson, O. | Rossing, P. | Schwartz, T. W. | Slagboom, P. E. | Sterner, M. | Tang, M. | Tarnow, L. | Tuomi, T. | van’t Riet, E. | van Leeuwen, N. | Varga, T. V. | Vestmar, M. A. | Walker, M. | Wang, B. | Wang, Y. | Wu, H. | Xi, F. | Yengo, L. | Yu, C. | Zhang, X. | Zhang, J. | Zhang, Q. | Zhang, W. | Zheng, H. | Zhou, Y. | Altshuler, D. | ‘t Hart, L. M. | Franks, P. W. | Balkau, B. | Froguel, P. | McCarthy, M. I. | Laakso, M. | Groop, L. | Christensen, C. | Brandslund, I. | Lauritzen, T. | Witte, D. R. | Linneberg, A. | Jørgensen, T. | Hansen, T. | Wang, J. | Nielsen, R. | Pedersen, O.
Diabetologia  2012;56(2):298-310.
Aims/hypothesis
Human complex metabolic traits are in part regulated by genetic determinants. Here we applied exome sequencing to identify novel associations of coding polymorphisms at minor allele frequencies (MAFs) >1% with common metabolic phenotypes.
Methods
The study comprised three stages. We performed medium-depth (8×) whole exome sequencing in 1,000 cases with type 2 diabetes, BMI >27.5 kg/m2 and hypertension and in 1,000 controls (stage 1). We selected 16,192 polymorphisms nominally associated (p < 0.05) with case–control status, from four selected annotation categories or from loci reported to associate with metabolic traits. These variants were genotyped in 15,989 Danes to search for association with 12 metabolic phenotypes (stage 2). In stage 3, polymorphisms showing potential associations were genotyped in a further 63,896 Europeans.
Results
Exome sequencing identified 70,182 polymorphisms with MAF >1%. In stage 2 we identified 51 potential associations with one or more of eight metabolic phenotypes covered by 45 unique polymorphisms. In meta-analyses of stage 2 and stage 3 results, we demonstrated robust associations for coding polymorphisms in CD300LG (fasting HDL-cholesterol: MAF 3.5%, p = 8.5 × 10−14), COBLL1 (type 2 diabetes: MAF 12.5%, OR 0.88, p = 1.2 × 10−11) and MACF1 (type 2 diabetes: MAF 23.4%, OR 1.10, p = 8.2 × 10−10).
Conclusions/interpretation
We applied exome sequencing as a basis for finding genetic determinants of metabolic traits and show the existence of low-frequency and common coding polymorphisms with impact on common metabolic traits. Based on our study, coding polymorphisms with MAF above 1% do not seem to have particularly high effect sizes on the measured metabolic traits.
Electronic supplementary material
The online version of this article (doi:10.1007/s00125-012-2756-1) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
doi:10.1007/s00125-012-2756-1
PMCID: PMC3536959  PMID: 23160641
Exome sequencing; Genetic epidemiology; Genetics; Lipids; Next-generation sequencing; Obesity; Type 2 diabetes
24.  Pinellia pedatisecta agglutinin interacts with the methylosome and induces cancer cell death 
Lu, Q | Li, N | Luo, J | Yu, M | Huang, Y | Wu, X | Wu, H | Liu, X Y | Li, G
Oncogenesis  2012;1(10):e29-.
Pinellia pedatisecta agglutinin (PPA) is a specific mannose-binding plant lectin accumulated in the tuber of P. pedatisecta. In the work presented, the cytotoxicity of PPA to cancer cells was investigated through exogenous expression. A PPA gene was transduced into normal and cancer cell lines through plasmid vectors, and the effect of PPA expression was examined. Results showed that PPA translocated into the nucleus, colocalized with DNA and induced cell death. A mannose-binding motif and a V103-W130 region directed the nuclear translocation of PPA. Coprecipitation, mass spectrometry and western blotting analysis further indentified that PPA was associated with the methylosome, which contains methylosome protein 50 and protein arginine methyltransferase 5 (PRMT5). Knockdown of PRMT5 significantly inhibited the PPA-induced cell death, suggesting that PPA used the methylosome as a target. Furthermore, Ad.surp-PPA, an adenovirus vector in which the PPA gene was controlled by a survivin promoter (surp), selectively inhibited the proliferation of cancer cell lines. Taken together, the expression of PPA gene elicited significant cytotoxicity to cancer cells through targeting the methylosome and might be developed into a novel agent in cancer gene therapy.
doi:10.1038/oncsis.2012.30
PMCID: PMC3503292  PMID: 23552401
methylosome; Pinellia pedatisecta agglutinin; MEP50; PRMT5; nuclear translocation
25.  Inter-unit variability in two ParvoMedics TrueOne 2400 automated metabolic gas analysis systems 
Knowing the inter-unit variability, especially the technological error, is important when using many physiological measurement systems, yet no such inter-unit analysis has been undertaken on duplicate automated gas analysis systems. This study investigated the inter-unit performance of two identical ParvoMedics TrueOne 2400 automated gas analysis systems during a range of submaximal steady-state exercises performed on an electromagnetic cycle ergometer. Fifteen adult males were tested on two separate days a rest, 30, 60, 90, and 120 Watts with the duplicate gas analysis units arranged (1) collaterally (2 min of steady-state expired gas was alternately passed through each system), and (2) simultaneously (identical steady-state expired gas was passed simultaneously through both systems). Total within-subject variation (biological + technological) was determined from the collateral tests, but the unique inter-unit variability (technological error between identical systems) was shown by the simultaneous tests. Absolute percentage errors (APE), coefficient of variations (CV), effect sizes and Bland–Altman analyses were undertaken on the metabolic data, including expired ventilation (VE), oxygen consumption (VO2) and carbon dioxide production (VCO2). The few statistically significant differences detected between the two duplicate systems were determined to have small or trivial effect sizes, and their magnitudes to be of little physiological importance. The total within-subject variations for VO2, VCO2 and VE each equated to a mean CV and mean APE value of ~4 and ~6 %, whilst the respective inter-unit technological errors equated to ~1.5 and ~2.1 %. The two ParvoMedics TrueOne 2400 systems demonstrated excellent inter-unit agreement.
doi:10.1007/s00421-012-2483-9
PMCID: PMC3569593  PMID: 22945269
Variation; Agreement; Technological error; ParvoMedics; Gas analysis

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