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1.  Establishing Magnetic Resonance Imaging as an Accurate and Reliable Tool to Diagnose and Monitor Esophageal Cancer in a Rat Model 
PLoS ONE  2014;9(4):e93694.
To assess the reliability of magnetic resonance imaging (MRI) for detection of esophageal cancer in the Levrat model of end-to-side esophagojejunostomy.
The Levrat model has proven utility in terms of its ability to replicate Barrett’s carcinogenesis by inducing gastroduodenoesophageal reflux (GDER). Due to lack of data on the utility of non-invasive methods for detection of esophageal cancer, treatment efficacy studies have been limited, as adenocarcinoma histology has only been validated post-mortem. It would therefore be of great value if the validity and reliability of MRI could be established in this setting.
Chronic GDER reflux was induced in 19 male Sprague-Dawley rats using the modified Levrat model. At 40 weeks post-surgery, all animals underwent endoscopy, MRI scanning, and post-mortem histological analysis of the esophagus and anastomosis. With post-mortem histology serving as the gold standard, assessment of presence of esophageal cancer was made by five esophageal specialists and five radiologists on endoscopy and MRI, respectively.
The accuracy of MRI and endoscopic analysis to correctly identify cancer vs. no cancer was 85.3% and 50.5%, respectively. ROC curves demonstrated that MRI rating had an AUC of 0.966 (p<0.001) and endoscopy rating had an AUC of 0.534 (p = 0.804). The sensitivity and specificity of MRI for identifying cancer vs. no-cancer was 89.1% and 80% respectively, as compared to 45.5% and 57.5% for endoscopy. False positive rates of MRI and endoscopy were 20% and 42.5%, respectively.
MRI is a more reliable diagnostic method than endoscopy in the Levrat model. The non-invasiveness of the tool and its potential to volumetrically quantify the size and number of tumors likely makes it even more useful in evaluating novel agents and their efficacy in treatment studies of esophageal cancer.
PMCID: PMC3976303  PMID: 24705451
2.  Metabotropic Glutamate Receptor-1 as a Novel Target for the Antiangiogenic Treatment of Breast Cancer 
PLoS ONE  2014;9(3):e88830.
Metabotropic glutamate receptors (mGluRs) are normally expressed in the central nervous system, where they mediate neuronal excitability and neurotransmitter release. Certain cancers, including melanoma and gliomas, express various mGluR subtypes that have been implicated as playing a role in disease progression. Recently, we detected metabotropic glutamate receptor-1 (gene: GRM1; protein: mGluR1) in breast cancer and found that it plays a role in the regulation of cell proliferation and tumor growth. In addition to cancer cells, brain endothelial cells express mGluR1. In light of these studies, and because angiogenesis is both a prognostic indicator in cancer correlating with a poorer prognosis and a potential therapeutic target, we explored a potential role for mGluR1 in mediating endothelial cell (EC) proliferation and tumor-induced angiogenesis. GRM1 and mGluR1 were detected in various types of human ECs and, using mGluR1-specific inhibitors or shRNA silencing, we demonstrated that EC growth and Matrigel tube formation are dependent on mGluR1 signaling. In addition, loss of mGluR1 activity leads to reduced angiogenesis in a murine Matrigel sponge implant model as well as a murine tumor model. These results suggest a role for mGluR1 in breast cancer as a pro-angiogenic factor as well as a mediator of tumor progression. They also suggest mGluR1 as a potential new molecular target for the anti-angiogenic therapy of breast cancer.
PMCID: PMC3954556  PMID: 24633367
3.  Epigenetic mechanisms and models in the origins of asthma 
Purpose of the review
Epigenetic mechanisms have the ability to alter the phenotype without changing the genetic code. The science of epigenetics has grown considerably in recent years, and future epigenetically-based treatments or prevention strategies are likely. Epigenetic associations with asthma have received growing interest because genetic and environmental factors have been unable to independently explain the etiology of asthma.
Recent Findings
Recent findings suggest that both the environment and underlying genetic sequence variation influence DNA methylation, which in turn seems to modify the risk conferred by genetic variants for various asthma phenotypes. In particular DNA methylation may act as an archive of a variety of early developmental exposures which then can modify the risk related to genetic variants.
Current asthma treatments may control the symptoms of asthma but do not modify its natural history. Epigenetic mechanisms and novel explanatory models provide burgeoning approaches to significantly increase our understanding of the initiation and progression of asthma. This will lead to critical information to prevent or treat asthma not only in the current generation, but due to the epigenetic inheritance may also prevent asthma in future generations.
PMCID: PMC3952069  PMID: 23242116
Asthma; Epigenetics; DNA methylation; methylation quantitative trait loci; modifiable genetic variants
4.  Focused Ultrasound-Mediated Drug Delivery from Microbubbles Reduces Drug Dose Necessary for Therapeutic Effect on Neointima Formation 
We hypothesized that 1) neointimal formation in a rat carotid balloon injury model could be reduced in vivo following targeted ultrasound delivery of rapamycin-loaded microbubbles (RMBs), and 2) the addition of dual mode ultrasound decreases the total amount of drug needed to reduce neointima formation.
Methods and Results
Balloon injury was performed in rat carotids to induce neointima formation. High or low doses of RMBs were injected I.V. and ruptured at the site of injury with ultrasound. Compared to non-treated injured arteries, neointima formation was reduced by 0% and 35.9% with 108 RMBs, and by 28.7% and 34.9% in arteries treated with 109 RMBs with and without ultrasound respectively.
Without ultrasound, 10-fold higher concentrations of RMBs were needed to reduce neointima formation by at least 28%, whereas 108 RMBs combined with ultrasound were sufficient to achieve the same therapeutic effect demonstrating that this technology may have promise for localized potent drug therapy.
PMCID: PMC3935345  PMID: 21960561
Balloon Injury; Ultrasound; Microbubbles; Drug Delivery; Rats
5.  Astronomical algorithms for automated analysis of tissue protein expression in breast cancer 
British Journal of Cancer  2013;108(3):602-612.
High-throughput evaluation of tissue biomarkers in oncology has been greatly accelerated by the widespread use of tissue microarrays (TMAs) and immunohistochemistry. Although TMAs have the potential to facilitate protein expression profiling on a scale to rival experiments of tumour transcriptomes, the bottleneck and imprecision of manually scoring TMAs has impeded progress.
We report image analysis algorithms adapted from astronomy for the precise automated analysis of IHC in all subcellular compartments. The power of this technique is demonstrated using over 2000 breast tumours and comparing quantitative automated scores against manual assessment by pathologists.
All continuous automated scores showed good correlation with their corresponding ordinal manual scores. For oestrogen receptor (ER), the correlation was 0.82, P<0.0001, for BCL2 0.72, P<0.0001 and for HER2 0.62, P<0.0001. Automated scores showed excellent concordance with manual scores for the unsupervised assignment of cases to ‘positive' or ‘negative' categories with agreement rates of up to 96%.
The adaptation of astronomical algorithms coupled with their application to large annotated study cohorts, constitutes a powerful tool for the realisation of the enormous potential of digital pathology.
PMCID: PMC3593538  PMID: 23329232
image analysis; immunohistochemistry; breast cancer; systems pathology; digital pathology
6.  Aspirin use and knowledge in the community: a population- and health facility based survey for measuring local health system performance 
Little is known about the relationship between cardiovascular risk, disease and actual use of aspirin in the community.
The Measuring Disparities in Chronic Conditions (MDCC) study is a community and health facility-based survey designed to track disparities in the delivery of health interventions for common chronic diseases. MDCC includes a survey instrument designed to collect detailed information about aspirin use. In King County, WA between 2011 and 2012, we surveyed 4633 white, African American, or Hispanic adults (45% home address-based sample, 55% health facility sample). We examined self-reported counseling on, frequency of use and risks of aspirin for all respondents. For a subgroup free of CAD or cerebral infarction that underwent physical examination, we measured 10-year coronary heart disease risk and blood salicylate concentration.
Two in five respondents reported using aspirin routinely while one in five with a history of CAD or cerebral infarction and without contraindication did not report routine use of aspirin. Women with these conditions used less aspirin than men (65.0% vs. 76.5%) and reported more health problems that would make aspirin unsafe (29.4% vs. 21.2%). In a subgroup undergoing phlebotomy a third of respondents with low cardiovascular risk used aspirin routinely and only 4.6% of all aspirin users had no detectable salicylate in their blood.
In this large urban county where health care delivery should be of high quality, there is insufficient aspirin use among those with high cardiovascular risk or disease and routine aspirin use by many at low risk. Further efforts are needed to promote shared-decision making between patients and clinicians as well as inform the public about appropriate use of routine aspirin to reduce the burden of atherosclerotic vascular disease.
PMCID: PMC3922250  PMID: 24507089
Aspirin; Prevention; Coronary disease
7.  β-Arrestin Interacts with the Beta/Gamma Subunits of Trimeric G-Proteins and Dishevelled in the Wnt/Ca2+ Pathway in Xenopus Gastrulation 
PLoS ONE  2014;9(1):e87132.
β-Catenin independent, non-canonical Wnt signaling pathways play a major role in the regulation of morphogenetic movements in vertebrates. The term non-canonical Wnt signaling comprises multiple, intracellularly divergent, Wnt-activated and β-Catenin independent signaling cascades including the Wnt/Planar Cell Polarity and the Wnt/Ca2+ cascades. Wnt/Planar Cell Polarity and Wnt/Ca2+ pathways share common effector proteins, including the Wnt ligand, Frizzled receptors and Dishevelled, with each other and with additional branches of Wnt signaling. Along with the aforementioned proteins, β-Arrestin has been identified as an essential effector protein in the Wnt/β-Catenin and the Wnt/Planar Cell Polarity pathway. Our results demonstrate that β-Arrestin is required in the Wnt/Ca2+ signaling cascade upstream of Protein Kinase C (PKC) and Ca2+/Calmodulin-dependent Protein Kinase II (CamKII). We have further characterized the role of β-Arrestin in this branch of non-canonical Wnt signaling by knock-down and rescue experiments in Xenopus embryo explants and analyzed protein-protein interactions in 293T cells. Functional interaction of β-Arrestin, the β subunit of trimeric G-proteins and Dishevelled is required to induce PKC activation and membrane translocation. In Xenopus gastrulation, β-Arrestin function in Wnt/Ca2+ signaling is essential for convergent extension movements. We further show that β-Arrestin physically interacts with the β subunit of trimeric G-proteins and Dishevelled, and that the interaction between β-Arrestin and Dishevelled is promoted by the beta/gamma subunits of trimeric G-proteins, indicating the formation of a multiprotein signaling complex.
PMCID: PMC3906129  PMID: 24489854
8.  Analytical modeling of glucose biosensors based on carbon nanotubes 
In recent years, carbon nanotubes have received widespread attention as promising carbon-based nanoelectronic devices. Due to their exceptional physical, chemical, and electrical properties, namely a high surface-to-volume ratio, their enhanced electron transfer properties, and their high thermal conductivity, carbon nanotubes can be used effectively as electrochemical sensors. The integration of carbon nanotubes with a functional group provides a good and solid support for the immobilization of enzymes. The determination of glucose levels using biosensors, particularly in the medical diagnostics and food industries, is gaining mass appeal. Glucose biosensors detect the glucose molecule by catalyzing glucose to gluconic acid and hydrogen peroxide in the presence of oxygen. This action provides high accuracy and a quick detection rate. In this paper, a single-wall carbon nanotube field-effect transistor biosensor for glucose detection is analytically modeled. In the proposed model, the glucose concentration is presented as a function of gate voltage. Subsequently, the proposed model is compared with existing experimental data. A good consensus between the model and the experimental data is reported. The simulated data demonstrate that the analytical model can be employed with an electrochemical glucose sensor to predict the behavior of the sensing mechanism in biosensors.
PMCID: PMC3898395  PMID: 24428818
Carbon nanotube; SWCNT FET; Glucose detection; Biosensor; Analytical model; I-V characteristics; PBS; Glucose oxide
9.  Impact of dietary oils and fats on lipid peroxidation in liver and blood of albino rats 
To investigate the effects of different dietary fat and oils (differing in their degree of saturation and unsaturation) on lipid peroxidation in liver and blood of rats.
The study was conducted on 50 albino rats that were randomly divided into 5 groups of 10 animals. The groups were fed on dietary butter (Group I), margarine (Group II), olive oil (Group III), sunflower oil (Group IV) and corn oil (Group V) for 7 weeks. After 12 h of diet removal, livers were excised and blood was collected to measure malondialdehyde (MDA) levels in the supernatant of liver homogenate and in blood. Blood superoxide dismutase activity (SOD), glutathione peroxidase activity (GPx), serum vitamin E and total antioxidant capacity (TAC) levels were also measured to determine the effects of fats and oils on lipid peroxidation.
The results indicated that no significant differences were observed in SOD activity, vitamin E and TAC levels between the five groups. However, there was significant decrease of GPx activity in groups IV and V when compared with other groups. The results indicated that feeding corn oil caused significant increases in liver and blood MDA levels as compared with other oils and fats. There were positive correlations between SOD and GPx, vitamin E and TAC as well as between GPx and TAC (r: 0.743; P<0.001) and between blood MDA and liver MDA (r: 0.897; P<0.001). The results showed also negative correlations between blood MDA on one hand and SOD, GPx, vitamin E and TAC on the other hand.
The results demonstrated that feeding oils rich in polyunsaturated fatty acids (PUFA) increases lipid peroxidation significantly and may raise the susceptibility of tissues to free radical oxidative damage.
PMCID: PMC3819496  PMID: 24144131
Vegetable oils; Butter; Margarine; Polyunsaturated fatty acids (PUFA); Lipid peroxidation; Malondialdehyde (MDA); Superoxide dismutase activity (SOD); Glutathione peroxidase activity (GPx)
10.  Combined choroidal neovascularization and hypopituitarism in a patient with homozygous mutation in methylenetetrahydrofolate reductase gene 
We report a case of choroidal neovascularization (CNV) secondary to methylenetetrahydrofolate reductase (MTHFR) gene mutation in a 20-year-old male patient with hypopituitarism. Treatment with three consecutive injections of intravitreal ranibizumab (anti-vascular endothelial growth factor) resulted in significant improvement of the patient's vision and the appearance of the macula. A search of the literature produced no previously reported case of MTHFR gene mutation associated both CNV and possibly hypopituitarism. With hormone replacement therapy of hypopituitarism, acetyl salicylic acid 100 mg/day also was started. The patient was clinically stable both for CNV and other thromboembolic disorders over a 6-month follow-up and also 1-year follow-up period.
PMCID: PMC3963328  PMID: 24672570
Choroidal neovascularization; drug therapy; hypopituitarism; intravitreal injections; methylenetetrahydrofolate reductase deficiency; MTHFR; ranibizumab; vascular endothelial growth factor
11.  Primary Subcutaneous Hydatid Cyst with Palisading Granulomatous Reaction 
Case Reports in Pathology  2013;2013:126541.
Palisading granulomatous reactions are prominent microscopic characteristics that are seen in many diseases. Isolated subcutaneous cystic echinococcosis is rarely documented. Palisading granuloma as a host immune reaction to Echinococcus granulosus in an isolated primary subcutaneous hydatid cyst has been reported only once before. In this report, we are describing a 53-year-old male who developed a slowly growing subcutaneous thigh mass. Light microscopy confirmed the presence of hydatid cyst. Further radiological workup for liver and lung has not shown any visceral hydatid focus.
PMCID: PMC3872406  PMID: 24386579
12.  Disparities in HIV Screening among Pregnant Women – El Salvador, 2011 
PLoS ONE  2013;8(12):e82760.
To provide an accurate estimate of antenatal HIV screening and its determinants among pregnant women in El Salvador and help local authorities make informed decisions for targeted interventions around mother-to-child transmission (MTCT).
A total sample of 4,730 women aged 15-49 years were interviewed from a random sample of 3,625 households. We collected data on antenatal care services, including HIV screening, during last pregnancy through a pre-established questionnaire. We used a backward elimination multivariate logistic regression model to examine the association between HIV screening and sociodemographic and health care-related factors.
A total of 2,929 women were included in this analysis. About 98% of participants reported receiving antenatal care, but only 83% of these reported being screened for HIV. Screening was lower in geographic areas with higher HIV incidence and ranged from 69.1% among women who were not seen by a physician during antenatal care, to 93.7% among those who attended or completed college. Odds for screening varied also by age, employment status, household economic expenditure, possession of health care coverage, health care settings, and number of antenatal care visits.
We found disparities in HIV screening during antenatal care at the environmental, social, demographic, and structural levels despite a high uptake of antenatal care in El Salvador. Our findings should urge health authorities to tailor and enhance current strategies implemented to eliminate MTCT and reduce inequities and HIV morbidity among women in El Salvador.
PMCID: PMC3857257  PMID: 24349356
Hand‐held dynamometers are commonly used to assess plantarflexor strength during rehabilitation. The purpose of this study was to determine the concurrent validity of measuring plantarflexion force using a hand‐held dynamometer (HHD) as compared to an electromechanical dynamometer as the gold standard. The hypothesis was that plantarflexor forces obtained using a hand‐held dynamometer would not show absolute agreement with a criterion standard.
Concurrent validity assessment for a diagnostic strength testing device.
Institutional clinic and research laboratory
Volunteer sample of healthy university students (N=20, 10 women, 10 men; 25.9±4.1 years).
Main Outcome Measure(s):
Maximal plantarflexion strength was measured using both a HHD and an electromechanical dynamometer (EMD) as a criterion measure.
Plantarflexor force measures with the HHD were significantly different (p<0.01) and not correlated with plantarflexor forces measured using the EMD for either limb (R2 ≤ 0.09).
Plantarflexor strength measurements acquired using HHD are different from those acquired using an EMD and are likely influenced by the strength of the examiner.
Level of Evidence:
Prospective cohort study, level II
PMCID: PMC3867075  PMID: 24377068
Diagnostic strength; triceps surae; concurrent validity
14.  Brain Iron Detected by SWI High Pass Filtered Phase Calibrated with Synchrotron X-Ray Fluorescence 
Journal of magnetic resonance imaging : JMRI  2010;31(6):10.1002/jmri.22201.
To test the ability of susceptibility weighted images (SWI) and high pass filtered phase images to localize and quantify brain iron.
Materials and Methods
Magnetic resonance (MR) images of human cadaver brain hemispheres were collected using a gradient echo based SWI sequence at 1.5T. For X-ray fluorescence (XRF) mapping, each brain was cut to obtain slices that reasonably matched the MR images and iron was mapped at the iron K-edge at 50 or 100 μm resolution. Iron was quantified using XRF calibration foils. Phase and iron XRF were averaged within anatomic regions of one slice, chosen for its range of iron concentrations and nearly perfect anatomic correspondence. X-ray absorption spectroscopy (XAS) was used to determine if the chemical form of iron was different in regions with poorer correspondence between iron and phase.
Iron XRF maps, SWI, and high pass filtered phase data in nine brain slices from five subjects were visually very similar, particularly in high iron regions. The chemical form of iron could not explain poor matches. The correlation between the concentration of iron and phase in the cadaver brain was estimated as cFe [μg/g tissue] = 850Δφ + 110.
The phase shift Δφ was found to vary linearly with iron concentration with the best correspondence found in regions with high iron content.
PMCID: PMC3843009  PMID: 20512886 CAMSID: cams3710
iron; phase imaging; x-ray fluorescence; susceptibility weighted imaging; human
15.  Epidemiologic Methods of Assessing Asthma and Wheezing Episodes in Longitudinal Studies: Measures of Change and Stability 
Journal of Epidemiology  2013;23(6):399-410.
In settings in which diseases wax and wane, there is a need to measure disease dynamics in longitudinal studies. Traditional measures of disease occurrence (eg, cumulative incidence) do not address change or stability or are limited to stable cohorts (eg, incidence) and may thus lead to erroneous conclusions. To illustrate how different measures can be used to detect disease dynamics, we investigated sex differences in the occurrence of asthma and wheezing, using a population-based study cohort that covered the first 18 years of life.
In the Isle of Wight birth cohort (n = 1456), prevalence, incidence, cumulative incidence, positive and negative transitions, and remission were determined at ages 1 or 2, 4, 10, and 18 years. Latent transition analysis was used to simultaneously identify classes of asthma and wheezing (related phenotypes) and characterize transition probabilities over time. Trajectory analysis was used to characterize the natural history of asthma and wheezing.
Regarding time-specific changes, positive and negative transition probabilities were more informative than other measures of associations because they revealed a sex switchover in asthma prevalence (P < 0.05). Transition probabilities were able to identify the origin of a sex-specific dynamic; in particular, prior wheezing transitioned to asthma at age 18 years among girls but not among boys. In comparison with latent transition analysis, trajectory analysis did not directly identify a switchover in prevalence among boys and girls.
In longitudinal analyses, transition analyses that impose minimal restrictions on data are needed in order to produce appropriate information on disease dynamics.
PMCID: PMC3834276  PMID: 23994864
asthma; cohort study; incidence; prevalence; trajectory; transition probability
16.  Prognostic Value and Targeted Inhibition of Survivin Expression in Esophageal Adenocarcinoma and Cancer-Adjacent Squamous Epithelium 
PLoS ONE  2013;8(11):e78343.
Survivin is an inhibitor of apoptosis and its over expression is associated with poor prognosis in several malignancies. While several studies have analyzed survivin expression in esophageal squamous cell carcinoma, few have focused on esophageal adenocarcinoma (EAC) and/or cancer-adjacent squamous epithelium (CASE). The purpose of this study was 1) to determine the degree of survivin up regulation in samples of EAC and CASE, 2) to evaluate if survivin expression in EAC and CASE correlates with recurrence and/or death, and 3) to examine the effect of survivin inhibition on apoptosis in EAC cells.
Fresh frozen samples of EAC and CASE from the same patient were used for qRT-PCR and Western blot analysis, and formalin-fixed, paraffin-embedded tissue was used for immunohistochemistry. EAC cell lines, OE19 and OE33, were transfected with small interfering RNAs (siRNAs) to knockdown survivin expression. This was confirmed by qRT-PCR for survivin expression and Western blot analysis of cleaved PARP, cleaved caspase 3 and survivin. Survivin expression data was correlated with clinical outcome.
Survivin expression was significantly higher in EAC tumor samples compared to the CASE from the same patient. Patients with high expression of survivin in EAC tumor had an increased risk of death. Survivin expression was also noted in CASE and correlated with increased risk of distant recurrence. Cell line evaluation demonstrated that inhibition of survivin resulted in an increase in apoptosis.
Higher expression of survivin in tumor tissue was associated with increased risk of death; while survivin expression in CASE was a superior predictor of recurrence. Inhibition of survivin in EAC cell lines further showed increased apoptosis, supporting the potential benefits of therapeutic strategies targeted to this marker.
PMCID: PMC3817247  PMID: 24223792
17.  Platelet-derived CD154: ultrastructural localization and clinical correlation in organ transplantation 
CD154 is an immunostimulatory ligand for CD40 that markedly influences alloimmunity. Its presence in platelets suggests that its release and subsequent immune effects are driven by trauma and thus could be relevant following organ transplantation. However, the release of platelet derived CD154 and its consequences have not been investigated in a clinical transplant setting. To better characterize the relationship between platelet activation and CD154 release, we investigated CD154 release by platelets obtained from normal individuals, and patients with two genetic defects that influence platelet granule development. Using these unique patient populations and immune-electron microscopy, we confirmed that CD154 was an alpha granule and not a cell surface protein, and thereafter optimized the methods for its in vivo measurement in humans. We then investigated plasma CD154 levels in kidney and liver transplant recipients and found no evidence that CD154 levels fluctuated systemically as a result of kidney or liver transplant procedures. Paradoxically, we found that kidney transplant patients had significantly lower systemic CD154 levels during episodes of rejection. These data suggest that the immune effects of CD154 are likely mediated through local and not systemic mechanisms, and discourage the use of CD154 as a peripheral biomarker in organ transplantation.
PMCID: PMC3484197  PMID: 22947105
platelets; co-stimulation; trauma
18.  Post-translational regulation enables robust p53 regulation 
BMC Systems Biology  2013;7:83.
The tumor suppressor protein p53 plays important roles in DNA damage repair, cell cycle arrest and apoptosis. Due to its critical functions, the level of p53 is tightly regulated by a negative feedback mechanism to increase its tolerance towards fluctuations and disturbances. Interestingly, the p53 level is controlled by post-translational regulation rather than transcriptional regulation in this feedback mechanism.
We analyzed the dynamics of this feedback to understand whether post-translational regulation provides any advantages over transcriptional regulation in regard to disturbance rejection. When a disturbance happens, even though negative feedback reduces the steady-state error, it can cause a system to become less stable and transiently overshoots, which may erroneously trigger downstream reactions. Therefore, the system needs to balance the trade-off between steady-state and transient errors. Feedback control and adaptive estimation theories revealed that post-translational regulation achieves a better trade-off than transcriptional regulation, contributing to a more steady level of p53 under the influence of noise and disturbances. Furthermore, post-translational regulation enables cells to respond more promptly to stress conditions with consistent amplitude. However, for better disturbance rejection, the p53- Mdm2 negative feedback has to pay a price of higher stochastic noise.
Our analyses suggest that the p53-Mdm2 feedback favors regulatory mechanisms that provide the optimal trade-offs for dynamic control.
PMCID: PMC3844394  PMID: 23992617
Feedback control theory; p53-Mdm2 feedback loop; Robustness; Disturbance rejection
After unilateral total knee arthroplasty (TKA), osteoarthritis (OA) in the non-operated often progresses. The altered gait mechanics exhibited by patients after TKA increase the loading on the non-operated knee and predispose it to disease progression. Therefore, our objective was to examine the potentially detrimental changes in frontal plane kinetics and kinematics during walking in patients who underwent unilateral TKA. Thirty one subjects six months after TKA, forty four subjects one year after unilateral TKA and twenty control subjects were recruited. All subjects underwent three dimensional gait analysis. In the TKA groups, the non-operated knee had a higher adduction angle and higher dynamic loading, knee adduction moment and impulse, compared to the operated knee. This increased loading may be an underlying reason for OA progression in the non-operated knee. Measures of loading in the control knee did not differ from that of the non-operated knee in the TKA group, but the TKA group walked with shorter step length. Whilst the non-operated knee loading was not different from controls, there may be greater risk of cumulative loading in the non-operated knee of the TKA group given their shorter step length.
PMCID: PMC3754839  PMID: 21437943
Physics in medicine and biology  2012;57(16):5275-5293.
Ultrasound-based real-time molecular imaging in large blood vessels holds promise for early detection and diagnosis of various important and significant diseases, such as stroke, atherosclerosis, and cancer. Central to the success of this imaging technique is the isolation of ligand-receptor bound adherent microbubbles from free microbubbles and tissue structures. In this paper, we present an alternative approach, termed singular spectrum-based targeted molecular (SiSTM) imaging, which separates signal components using singular value spectra content over local regions of complex echo data. Simulations were performed to illustrate the effects of acoustic target motion and harmonic energy on SiSTM imaging-derived measurements of statistical dimensionality. In vitro flow phantom experiments were performed under physiologically realistic conditions (2.7 cm/s flow velocity and 4 mm diameter) with targeted and non-targeted phantom channels. Both simulation and experimental results demonstrated that the relative motion and harmonic characteristics of adherent microbubbles (i.e. low motion and large harmonics) yields echo data with dimensionality that is distinct from free microbubbles (i.e. large motion and large harmonics) and tissue (i.e. low motion and low harmonics). Experimental SiSTM images produced the expected trend of greater adherent microbubble signal in targeted versus non-targeted microbubble experiments (P < 0.05, n = 4). The location of adherent microbubbles was qualitatively confirmed via optical imaging of fluorescent DiI signal along the phantom channel walls after SiSTM imaging. In comparison with two frequency-based real-time molecular imaging strategies, SiSTM imaging provided significantly higher image contrast (P < 0.001, n = 4) and larger area under the receiver operating characteristic curve (P < 0.05, n = 4).
PMCID: PMC3440015  PMID: 22853933
21.  The BMP Inhibitor Coco Reactivates Breast Cancer Cells at Lung Metastatic sites 
Cell  2012;150(4):764-779.
The mechanistic underpinnings of metastatic dormancy and reactivation are poorly understood. A gain-of-function cDNA screen reveals that Coco, a secreted antagonist of TGF-β ligands, induces dormant breast cancer cells to undergo reactivation in the lung. Mechanistic studies indicate that Coco exerts this effect by blocking lung-derived BMP ligands. Whereas Coco enhances the manifestation of traits associated with cancer stem cells, BMP signaling suppresses it. Coco induces a discrete gene expression signature, which is strongly associated with metastatic relapse to the lung but not to the bone or brain in patients. Experiments in mouse models suggest that these latter organs contain niches devoid of bioactive BMP. These findings reveal that metastasis-initiating cells need to overcome organ-specific anti-metastatic signals in order to undergo reactivation.
PMCID: PMC3711709  PMID: 22901808
22.  GDF3 is a BMP inhibitor that can activate Nodal signaling only at very high doses 
Developmental biology  2008;325(1):43-48.
Within the TGF-β superfamily, there are approximately forty ligands divided into two major branches: the TGF-β/Activin/Nodal ligands and the BMP/GDF ligands. We studied the ligand GDF3 and found that it inhibits signaling by its co-family members, the BMPs; however, GDF3 has been described by others to have Nodal-like activity. Here, we show that GDF3 can activate Nodal signaling, but only at very high doses and only upon mRNA over-expression. In contrast, GDF3 inhibits BMP signaling upon over-expression of GDF3 mRNA, as recombinant protein, and regardless of its dose. We therefore further characterized the mechanism through which GDF3 protein acts as a specific BMP inhibitor and found that the BMP inhibitory activity of GDF3 resides redundantly in the unprocessed, predominant form and in the mature form of the protein. These results confirm and extend the activity that we described for GDF3 and illuminate the experimental basis for the different observations of others. We suggest that GDF3 is either a bi-functional TGF-β ligand, or, more likely, that it is a BMP inhibitor that can artificially activate Nodal signaling under non-physiological conditions.
PMCID: PMC3740937  PMID: 18823971
GDF3; BMP; TGF-β; Embryo
23.  Left behind: widening disparities for males and females in US county life expectancy, 1985–2010 
The United States spends more than any other country on health care. The poor relative performance of the US compared to other high-income countries has attracted attention and raised questions about the performance of the US health system. An important dimension to poor national performance is the large disparities in life expectancy.
We applied a mixed effects Poisson statistical model and Gaussian Process Regression to estimate age-specific mortality rates for US counties from 1985 to 2010. We generated uncertainty distributions for life expectancy at each age using standard simulation methods.
Female life expectancy in the United States increased from 78.0 years in 1985 to 80.9 years in 2010, while male life expectancy increased from 71.0 years in 1985 to 76.3 years in 2010. The gap between female and male life expectancy in the United States was 7.0 years in 1985, narrowing to 4.6 years in 2010. For males at the county level, the highest life expectancy steadily increased from 75.5 in 1985 to 81.7 in 2010, while the lowest life expectancy remained under 65. For females at the county level, the highest life expectancy increased from 81.1 to 85.0, and the lowest life expectancy remained around 73. For male life expectancy at the county level, there have been three phases in the evolution of inequality: a period of rising inequality from 1985 to 1993, a period of stable inequality from 1993 to 2002, and rising inequality from 2002 to 2010. For females, in contrast, inequality has steadily increased during the 25-year period. Compared to only 154 counties where male life expectancy remained stagnant or declined, 1,405 out of 3,143 counties (45%) have seen no significant change or a significant decline in female life expectancy from 1985 to 2010. In all time periods, the lowest county-level life expectancies are seen in the South, the Mississippi basin, West Virginia, Kentucky, and selected counties with large Native American populations.
The reduction in the number of counties where female life expectancy at birth is declining in the most recent period is welcome news. However, the widening disparities between counties and the slow rate of increase compared to other countries should be viewed as a call for action. An increased focus on factors affecting health outcomes, morbidity, and mortality such as socioeconomic factors, difficulty of access to and poor quality of health care, and behavioral, environmental, and metabolic risk factors is urgently required.
PMCID: PMC3717281  PMID: 23842281
24.  Prevalence of physical activity and obesity in US counties, 2001–2011: a road map for action 
Obesity and physical inactivity are associated with several chronic conditions, increased medical care costs, and premature death.
We used the Behavioral Risk Factor Surveillance System (BRFSS), a state-based random-digit telephone survey that covers the majority of United States counties, and the National Health and Nutrition Examination Survey (NHANES), a nationally representative sample of the US civilian noninstitutionalized population. About 3.7 million adults aged 20 years or older participated in the BRFSS from 2000 to 2011, and 30,000 adults aged 20 or older participated in NHANES from 1999 to 2010. We calculated body mass index (BMI) from self-reported weight and height in the BRFSS and adjusted for self-reporting bias using NHANES. We calculated self-reported physical activity—both any physical activity and physical activity meeting recommended levels—from self-reported data in the BRFSS. We used validated small area estimation methods to generate estimates of obesity and physical activity prevalence for each county annually for 2001 to 2011.
Our results showed an increase in the prevalence of sufficient physical activity from 2001 to 2009. Levels were generally higher in men than in women, but increases were greater in women than men. Counties in Kentucky, Florida, Georgia, and California reported the largest gains. This increase in level of activity was matched by an increase in obesity in almost all counties during the same time period. There was a low correlation between level of physical activity and obesity in US counties. From 2001 to 2009, controlling for changes in poverty, unemployment, number of doctors per 100,000 population, percent rural, and baseline levels of obesity, for every 1 percentage point increase in physical activity prevalence, obesity prevalence was 0.11 percentage points lower.
Our study showed that increased physical activity alone has a small impact on obesity prevalence at the county level in the US. Indeed, the rise in physical activity levels will have a positive independent impact on the health of Americans as it will reduce the burden of cardiovascular diseases and diabetes. Other changes such as reduction in caloric intake are likely needed to curb the obesity epidemic and its burden.
PMCID: PMC3718620  PMID: 23842197
Physical activity; Obesity; Small area measurement; US counties
25.  Interactive effect of STAT6 and IL13 gene polymorphisms on eczema status: results from a longitudinal and a cross-sectional study 
BMC Medical Genetics  2013;14:67.
Eczema is a prevalent skin disease that is mainly characterized by systemic deviation of immune response and defective epidermal barrier. Th2 cytokines, such as IL-13 and transcription factor STAT6 are key elements in the inflammatory response that characterize allergic disorders, including eczema. Previous genetic association studies showed inconsistent results for the association of single nucleotide polymorphisms (SNPs) with eczema. Our aim was to investigate whether SNPs in IL13 and STAT6 genes, which share a biological pathway, have an interactive effect on eczema risk.
Data from two independent population-based studies were analyzed, namely the Isle of Wight birth cohort study (IOW; n = 1,456) and for the purpose of replication the Swansea PAPA (Poblogaeth Asthma Prifysgol Abertawe; n = 1,445) cross-sectional study. Log-binomial regressions were applied to (i) account for the interaction between IL13 (rs20541) and STAT6 (rs1059513) polymorphisms and (ii) estimate the combined effect, in terms of risk ratios (RRs), of both risk factors on the risk of eczema.
Under a dominant genetic model, the interaction term [IL13 (rs20541) × STAT6 (rs1059513)] was statistically significant in both studies (IOW: adjusted Pinteraction = 0.046; PAPA: Pinteraction = 0.037). The assessment of the combined effect associated with having risk genotypes in both SNPs yielded a 1.52-fold increased risk of eczema in the IOW study (95% confidence interval (CI): 1.05 – 2.20; P = 0.028) and a 2.01-fold higher risk of eczema (95% CI: 1.29 – 3.12; P = 0.002) in the PAPA study population.
Our study adds to the current knowledge of genetic susceptibility by demonstrating for the first time an interactive effect between SNPs in IL13 (rs20541) and STAT6 (rs1059513) on the occurrence of eczema in two independent samples. Findings of this report further support the emerging evidence that points toward the existence of genetic effects that occur via complex networks involving gene-gene interactions (epistasis).
PMCID: PMC3700873  PMID: 23815671
Eczema; Gene-gene Interaction; Epistasis; STAT6; IL13; Genetic Association Study

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