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1.  FGF receptor genes and breast cancer susceptibility: results from the Breast Cancer Association Consortium 
Agarwal, D | Pineda, S | Michailidou, K | Herranz, J | Pita, G | Moreno, L T | Alonso, M R | Dennis, J | Wang, Q | Bolla, M K | Meyer, K B | Menéndez-Rodríguez, P | Hardisson, D | Mendiola, M | González-Neira, A | Lindblom, A | Margolin, S | Swerdlow, A | Ashworth, A | Orr, N | Jones, M | Matsuo, K | Ito, H | Iwata, H | Kondo, N | Hartman, M | Hui, M | Lim, W Y | T-C Iau, P | Sawyer, E | Tomlinson, I | Kerin, M | Miller, N | Kang, D | Choi, J-Y | Park, S K | Noh, D-Y | Hopper, J L | Schmidt, D F | Makalic, E | Southey, M C | Teo, S H | Yip, C H | Sivanandan, K | Tay, W-T | Brauch, H | Brüning, T | Hamann, U | Dunning, A M | Shah, M | Andrulis, I L | Knight, J A | Glendon, G | Tchatchou, S | Schmidt, M K | Broeks, A | Rosenberg, E H | van't Veer, L J | Fasching, P A | Renner, S P | Ekici, A B | Beckmann, M W | Shen, C-Y | Hsiung, C-N | Yu, J-C | Hou, M-F | Blot, W | Cai, Q | Wu, A H | Tseng, C-C | Van Den Berg, D | Stram, D O | Cox, A | Brock, I W | Reed, M W R | Muir, K | Lophatananon, A | Stewart-Brown, S | Siriwanarangsan, P | Zheng, W | Deming-Halverson, S | Shrubsole, M J | Long, J | Shu, X-O | Lu, W | Gao, Y-T | Zhang, B | Radice, P | Peterlongo, P | Manoukian, S | Mariette, F | Sangrajrang, S | McKay, J | Couch, F J | Toland, A E | Yannoukakos, D | Fletcher, O | Johnson, N | Silva, I dos Santos | Peto, J | Marme, F | Burwinkel, B | Guénel, P | Truong, T | Sanchez, M | Mulot, C | Bojesen, S E | Nordestgaard, B G | Flyer, H | Brenner, H | Dieffenbach, A K | Arndt, V | Stegmaier, C | Mannermaa, A | Kataja, V | Kosma, V-M | Hartikainen, J M | Lambrechts, D | Yesilyurt, B T | Floris, G | Leunen, K | Chang-Claude, J | Rudolph, A | Seibold, P | Flesch-Janys, D | Wang, X | Olson, J E | Vachon, C | Purrington, K | Giles, G G | Severi, G | Baglietto, L | Haiman, C A | Henderson, B E | Schumacher, F | Le Marchand, L | Simard, J | Dumont, M | Goldberg, M S | Labrèche, F | Winqvist, R | Pylkäs, K | Jukkola-Vuorinen, A | Grip, M | Devilee, P | Tollenaar, R A E M | Seynaeve, C | García-Closas, M | Chanock, S J | Lissowska, J | Figueroa, J D | Czene, K | Eriksson, M | Humphreys, K | Darabi, H | Hooning, M J | Kriege, M | Collée, J M | Tilanus-Linthorst, M | Li, J | Jakubowska, A | Lubinski, J | Jaworska-Bieniek, K | Durda, K | Nevanlinna, H | Muranen, T A | Aittomäki, K | Blomqvist, C | Bogdanova, N | Dörk, T | Hall, P | Chenevix-Trench, G | Easton, D F | Pharoah, P D P | Arias-Perez, J I | Zamora, P | Benítez, J | Milne, R L
British Journal of Cancer  2014;110(4):1088-1100.
Breast cancer is one of the most common malignancies in women. Genome-wide association studies have identified FGFR2 as a breast cancer susceptibility gene. Common variation in other fibroblast growth factor (FGF) receptors might also modify risk. We tested this hypothesis by studying genotyped single-nucleotide polymorphisms (SNPs) and imputed SNPs in FGFR1, FGFR3, FGFR4 and FGFRL1 in the Breast Cancer Association Consortium.
Data were combined from 49 studies, including 53 835 cases and 50 156 controls, of which 89 050 (46 450 cases and 42 600 controls) were of European ancestry, 12 893 (6269 cases and 6624 controls) of Asian and 2048 (1116 cases and 932 controls) of African ancestry. Associations with risk of breast cancer, overall and by disease sub-type, were assessed using unconditional logistic regression.
Little evidence of association with breast cancer risk was observed for SNPs in the FGF receptor genes. The strongest evidence in European women was for rs743682 in FGFR3; the estimated per-allele odds ratio was 1.05 (95% confidence interval=1.02–1.09, P=0.0020), which is substantially lower than that observed for SNPs in FGFR2.
Our results suggest that common variants in the other FGF receptors are not associated with risk of breast cancer to the degree observed for FGFR2.
PMCID: PMC3929867  PMID: 24548884
breast cancer; SNP; FGF receptors; susceptibility; disease subtypes
2.  Effects of Bedding Material Composition in Deep Litter Systems on Bedding Characteristics and Growth Performance of Limousin Calves 
The objective of this study was to evaluate the effects of different litter mixture compositions on bedding system temperature, pH and volatile fatty acid and ammonia-N (NH3-N) content, and the serum physico-chemical parameters and growth indices of calves. Thirty-two Limousin calves (280±20 kg) were randomly assigned to four groups (n = 8 for each group) according to the bedding system used: i) control with soil only (CTR); ii) mixture with 50% paddy hulls (PH), 30% saw dusts (SD), 10% peat moss (PM) and 10% corn cobs (CC) (TRT1); iii) mixture with 15% PH, 15% SD, 10% PM, 40% CC, and 20% corn stover (CS) (TRT2); iv) mixture with 30% PH, 10% PM, 40% CC, and 20% CS (TRT3). The litter material combinations of different treatments were based on the cost of bedding system materials in China. The cost of four treatments from low to high: Control
PMCID: PMC4283184  PMID: 25557686
Bedding Systems; Volatile Fatty Acids; Serum Physico-chemical Parameters; Ammonia-N; Limousin Calves
Clinical oral investigations  2012;17(8):10.1007/s00784-012-0880-4.
Reports of osteonecrosis of the jaw (ONJ) have associated this lesion to treatment with bisphosphonates (BPs) and dental procedures. In this study, we investigated the association of specific dental diagnoses and procedures with ONJ among patients with past BP use.
Dentists from three Practice-Based Research Networks provided ONJ cases and controls (1:3). Data gathered from patients and dental offices with two respective standard questionnaires included demographic, medical, pharmaceutical, and dental information. Diagnoses and procedures up to three years prior to ONJ (prior to interview for controls) were analyzed within risk strata, defined by BP use and cancer status, using interaction terms within conditional logistic regression models.
We enrolled 191 ONJ cases and 573 controls from 119 dental offices. Among participants who had used only oral BP, extraction was the only dental risk factor for ONJ (OR=12, p=0.01). Suppuration was also more prevalent in cases (18%) than in controls (9%), but not statistically significant (OR=9, p=0.06).
Among participants who had not used either oral or IV BP (a majority of whom received RT to the head and neck), suppuration was the only dental risk factor for ONJ (prevalence=34% for cases and 8% for controls; OR=7, p=0.01). The prevalence of extractions in this group was also higher, but not statistically significant (44% vs 10%; OR=3). Limited power precludes definitive findings among participants exposed to IV BP.
Among patients taking oral BP, extraction was the only dental procedure associated with subsequent ONJ development.
Clinical Relevance
Results of this study suggest that routine dental procedures are not associated with development of ONJ in patients exposed to BPs.
PMCID: PMC3594331  PMID: 23212125
Osteonecrosis; jaws; bisphosphonates; dental diagnosis; dental treatment; risk factors
Increasing cost and scarcity of maize has stimulated the use of alternative feed sources (AFS) in the diets of cattle. In this study, we investigated the effects of partial or total replacement of maize on nutrient digestibility, growth performance, blood metabolites, and economics in Limousin crossbred feedlot cattle. Forty-five Limousin×Luxi crossbred bulls were randomly assigned to the three treatment groups, orthodox diet (OD; 45.0% maize), partial replacement diet (PRD; 15% maize, 67% AFS), total replacement diet (TRD; 0% maize, 100% AFS). The growth feeding trial lasted for 98 days. Dry matter intake (DMI) and average daily gain (ADG) were recorded. The digestion trial was carried out after the end of the growth trial. Total faeces and feed samples were measured daily. Digestibilities of dry matter (DM) and organic matter (OM), crude protein (CP), neutral detergent fiber (NDF) and acid detergent fiber (ADF) were calculated. After the feeding trial, blood metabolites were measured in 12 animals from each group. Initial and final body weights did not differ significantly among treatment groups (p>0.05). The ADG and DMI were 1.72 and 8.66, 1.60 and 9.10, and 1.40 and 9.11 kg/d for OD, PRD, and TRD, respectively. The PRD and TRD exhibited lower ADG (p<0.01) and higher DMI (p<0.01) than OD. The DMI (%body weight) was comparable between groups (p>0.5). Feed efficiency of PRD and TRD were lower than OD (p<0.01). The DM digestibility decreased with reduced level of maize (p = 0.10), OM digestibility was higher in OD (p<0.05), and CP, NDF and ADF digestibilities were similar for all groups (p>0.05). Blood urea nitrogen (mg/dL) in PRD and TRD was higher than OD (p<0.01), while other blood parameters did not differ significantly. Feed costs ($/head/d) were 1.49, 0.98, and 0.72 for OD, PRD, and TRD, respectively (p<0.01). Feed costs per kg gain ($) were significantly lower for PRD (0.63) and TRD (0.54) than OD (0.89; p<0.01). Overall profit ($/head) and daily profit ($/head/d) did not differ significantly between treatments (p>0.05), although TRD showed the highest economic benefits overall (p<0.01). While a traditional diet maximized the growth rate, partial or total replacement of dietary maize with AFS proved economically feasible due to their lower costs and comparable nutrient digestibilities of DM, CP, NDF, and ADF. Partial replacement may prove economically competitive in the current situation of China.
PMCID: PMC4150177  PMID: 25178296
Limousin Crossbred Cattle; Alternative Feed Sources; Growing Performance; Nutrient Digestibility; Blood Metabolites
Gene therapy  2004;11(7):609-618.
Site-specific recombination tools such as the Cre–loxP system are used to create animal models where conditional gene deletion/activation studies are required. In the current proof of principle study, we have demonstrated that a PET reporter gene (PRG), the herpes simplex virus type 1 thymidine kinase (HSV1-tk), can be made to remain silent and can be activated by Cre–loxP-mediated recombination in cell culture and in living mice. An adenovirus carrying a silent HSV1-tk was tail-vein injected (1×109 PFU) in six transgenic mice that express Cre recombinase in their liver (Cre+) and in four control mice (Cre−). The liver-specific expression of the PRG in Cre+ mice was detected in the microPET following injection of the reporter probe, 9-[4-fluoro-3-(hydroxymethyl)butyl]guanine ([18F]-FHBG). The [18F]-FHBG accumulation in the liver in terms of percent-injected dose per gram of tissue was 7.72±1.13 for the Cre+ mice and 0.10±0.02 for the Cre− mice (P<0.05) 48 h after adenoviral injection. These results were further validated by quantitative RT-PCR, western blotting and by in vitro assays for herpes simplex virus type 1 thymidine kinase enzyme activity. Thus by using the Cre–loxP system it is possible to modulate a PRG and noninvasively monitor the extent of Cre–loxP-mediated gene activation by imaging in a microPET scanner.
PMCID: PMC4141556  PMID: 14724687
Cre recombinase; Cre–loxP system; positron emission tomography reporter gene; herpes simplex virus type 1 thymidine kinase; noninvasive imaging; conditional gene activation/deletion
The monoamine serotonin (5-hydroxytryptamine, 5-HT), a well-known neurotransmitter, also has important functions outside the central nervous system. The objective of this study was to investigate the role of 5-HT in the proliferation, differentiation, and function of osteoblasts in vitro. We treated rat primary calvarial osteoblasts with various concentrations of 5-HT (1 nM to 10 µM) and assessed the rate of osteoblast proliferation, expression levels of osteoblast-specific proteins and genes, and the ability to form mineralized nodules. Next, we detected which 5-HT receptor subtypes were expressed in rat osteoblasts at different stages of osteoblast differentiation. We found that 5-HT could inhibit osteoblast proliferation, differentiation, and mineralization at low concentrations, but this inhibitory effect was mitigated at relatively high concentrations. Six of the 5-HT receptor subtypes (5-HT1A, 5-HT1B, 5-HT1D, 5-HT2A, 5-HT2B, and 5-HT2C) were found to exist in rat osteoblasts. Of these, 5-HT2A and 5-HT1B receptors had the highest expression levels, at both early and late stages of differentiation. Our results indicated that 5-HT can regulate osteoblast proliferation and function in vitro.
PMCID: PMC4143203  PMID: 25098615
Serotonin; Osteoblast; Proliferation; Differentiation; 5-HT receptors; 5-HT
Public health  2013;127(6):546-553.
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.
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.
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.\
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.
PMCID: PMC4086459  PMID: 23583033
Chronic; Physical health illnesses; Children; Race and ethnicity; Asthma; Hearing and vision; Health disparities
Luo, W | Wu, H | Ye, Y | Li, Z | Hao, S | Kong, L | Zheng, X | Lin, S | Nie, Q | Zhang, X
Cell Death & Disease  2014;5(7):e1347-.
Previous studies have shown that miR-203 is a skin-specific microRNA (miRNA) with a profound role in skin cell differentiation. However, emerging microarray and deep sequencing data revealed that miR-203 is also expressed in embryonic skeletal muscle and myoblasts. In this study, we found that miR-203 was transiently upregulated in chicken embryos on days 10 to 16 (E10–E16) and was sharply downregulated and even not expressed after E16 in chicken embryonic skeletal muscle. Histological profiles and weight variations of embryo skeletal muscle revealed that miR-203 expression is correlated with muscle development. In vitro experiments showed that miR-203 exhibited downregulated expression during myoblast differentiation into myotubes. miR-203 overexpression inhibited myoblast proliferation and differentiation, whereas its loss-of-function increased myoblast proliferation and differentiation. During myogenesis, miR-203 can target and inhibit the expression of c-JUN and MEF2C, which were important for cell proliferation and muscle development, respectively. The overexpression of c-JUN significantly promoted myoblast proliferation. Conversely, knockdown of c-JUN by siRNA suppressed myoblast proliferation. In addition, the knockdown of MEF2C by siRNA significantly inhibited myoblast differentiation. Altogether, these data not only suggested that the expression of miR-203 is transitory during chicken skeletal muscle development but also showed a novel role of miR-203 in inhibiting skeletal muscle cell proliferation and differentiation by repressing c-JUN and MEF2C, respectively.
PMCID: PMC4123083  PMID: 25032870
British Journal of Cancer  2013;108(9):1778-1783.
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.
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.
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).
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.
PMCID: PMC3658521  PMID: 23612451
benign prostatic hyperplasia; prostatitis; diabetes; interaction; prostate cancer
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.
PMCID: PMC3980210  PMID: 24704997
salicylate; inferior colliculus; auditory cortex; activity-dependent cytoskeletal protein; early growth response gene-1
Chen, J | Deng, D | Zhong, H | Lin, X | Kang, Y | Wu, H | Yan, J | Mai, G
Eye  2012;27(3):382-386.
To evaluate the feasibility and safety of a revised technique of botulinum toxin type A (BTA) injections for the treatment of infantile esotropia.
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.
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%).
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.
PMCID: PMC3597871  PMID: 23238444
botulinum toxin; infantile esotropia; sodium hyaluronate; complication
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.
PMCID: PMC3972701  PMID: 24658372
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.
PMCID: PMC3929313  PMID: 24563691
computerized tomography; diffusion maps; graph denoising; principal component analysis; Wiener filtering; Jaccard index; small world graph; Shepp–Logan phantom
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.
PMCID: PMC3715030  PMID: 23219911
sarco-endoplasmic reticulum Ca2+-ATPase; Ca2+ homeostasis; neuropathic pain; endoplasmic reticulum; sensory neuron
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.
PMCID: PMC3904554  PMID: 24060820
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.
PMCID: PMC3886882  PMID: 24415793
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.
PMCID: PMC3855850  PMID: 23069657
DNA damage; p53; inflammation; cirrhosis; hepatocellular carcinoma
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.
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.
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.
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.
PMCID: PMC3877431  PMID: 24366371
ghrelin receptor; HFCS; macrophages; inflammation; insulin resistance; liver steatosis
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.
PMCID: PMC4093821  PMID: 25049749
Montmorillonite; Growth Performance; Hematological Parameters; Bone Mineralization; Weaned Pig
Journal of microscopy  2010;241(2):10.1111/j.1365-2818.2010.03443.x.
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.
PMCID: PMC3807600  PMID: 21902693
Image restoration; microscopy imaging; microscope lens; transverse chromatic aberration
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.
PMCID: PMC3859330  PMID: 23903686
Hepatitis B virus; Genotype; Core promoter; Precore; Mutation; Advanced liver disease
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.
PMCID: PMC3730170  PMID: 23903555
Ye, J | Wu, H | Wu, Y | Wang, C | Zhang, H | Shi, X | Yang, J
Eye  2012;26(7):1012-1020.
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).
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.
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.
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.
PMCID: PMC3396180  PMID: 22595911
hyaluronan; EDTA; DNA damage; ROS; corneal epithelial cell
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.
PMCID: PMC3730425  PMID: 23868064
Sirt3; OGG1; mitochondria; DNA repair; apoptosis

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