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1.  Population-specific frequencies for LRRK2 susceptibility variants in the Genetic Epidemiology Of Parkinson’s Disease (GEO-PD) consortium 
Variants within the leucine-rich repeat kinase 2 gene are recognized as the most frequent genetic cause of Parkinson’s disease. Leucine-rich repeat kinase 2 variation related to susceptibility to disease displays many features that reflect the nature of complex late-onset sporadic disorders, such as Parkinson’s disease. The Genetic Epidemiology of Parkinson’s disease consortium recently performed the largest genetic association study for variants in the leucine-rich repeat kinase 2 gene across 23 different sites in 15 countries. Herein we detail the allele frequencies for the novel risk factors (p.A419V and p.M1646T) and the protective haplotype (p.N551K-R1398H-K1423K) reported in the original publication. Simple population allele frequencies can not only provide an insight into the clinical relevance of specific variants but also help genetically define patient groups. Establishing individual patient-based genomic susceptibility profiles incorporating both risk and protective factors will determine future diagnostic and treatment strategies.
PMCID: PMC4108155  PMID: 23913756
Parkinson disease; LRRK2; genetics; association study
2.  On the origins of the mitotic shift in proliferating cell layers 
During plant and animal development, monolayer cell sheets display a stereotyped distribution of polygonal cell shapes. In interphase cells these shapes range from quadrilaterals to decagons, with a robust average of six sides per cell. In contrast, the subset of cells in mitosis exhibits a distinct distribution with an average of seven sides. It remains unclear whether this ‘mitotic shift’ reflects a causal relationship between increased polygonal sidedness and increased division likelihood, or alternatively, a passive effect of local proliferation on cell shape.
We use a combination of probabilistic analysis and mathematical modeling to predict the geometry of mitotic polygonal cells in a proliferating cell layer. To test these predictions experimentally, we use Flp-Out stochastic labeling in the Drosophila wing disc to induce single cell clones, and confocal imaging to quantify the polygonal topologies of these clones as a function of cellular age. For a more generic test in an idealized cell layer, we model epithelial sheet proliferation in a finite element framework, which yields a computationally robust, emergent prediction of the mitotic cell shape distribution.
Using both mathematical and experimental approaches, we show that the mitotic shift derives primarily from passive, non-autonomous effects of mitoses in neighboring cells on each cell’s geometry over the course of the cell cycle. Computationally, we predict that interphase cells should passively gain sides over time, such that cells at more advanced stages of the cell cycle will tend to have a larger number of neighbors than those at earlier stages. Validating this prediction, experimental analysis of randomly labeled epithelial cells in the Drosophila wing disc demonstrates that labeled cells exhibit an age-dependent increase in polygonal sidedness. Reinforcing these data, finite element simulations of epithelial sheet proliferation demonstrate in a generic framework that passive side-gaining is sufficient to generate a mitotic shift.
Taken together, our results strongly suggest that the mitotic shift reflects a time-dependent accumulation of shared cellular interfaces over the course of the cell cycle. These results uncover fundamental constraints on the relationship between cell shape and cell division that should be general in adherent, polarized cell layers.
PMCID: PMC4048254  PMID: 24886286
Cell topology; Epithelial morphogenesis; Mathematical modeling; Mitosis; Developmental biology
3.  Control of the mitotic cleavage plane by local epithelial topology 
Cell  2011;144(3):427-438.
For nearly 150 years, it has been recognized that cell shape strongly influences the orientation of the mitotic cleavage plane (e.g. Hofmeister, 1863). However, we still understand little about the complex interplay between cell shape and cleavage plane orientation in epithelia, where polygonal cell geometries emerge from multiple factors, including cell packing, cell growth, and cell division itself. Here, using mechanical simulations, we show that the polygonal shapes of individual cells can systematically bias the long axis orientations of their adjacent mitotic neighbors. Strikingly, analysis of both animal epithelia and plant epidermis confirm a robust and nearly identical correlation between local cell topology and cleavage plane orientation in vivo. Using simple mathematics, we show that this effect derives from fundamental packing constraints. Our results suggest that local epithelial topology is a key determinant of cleavage plane orientation, and that cleavage plane bias may be a widespread property of polygonal cell sheets in plants and animals.
PMCID: PMC3491649  PMID: 21295702
4.  LRRK2 exonic variants and susceptibility to Parkinson’s disease 
Lancet neurology  2011;10(10):898-908.
Leucine-rich repeat kinase 2 (LRRK2) is known to harbor highly penetrant mutations linked to familial parkinsonism. However, its full polymorphic variability in relationship to Parkinson’s disease (PD) risk has not been systematically assessed.
We examined the frequency pathogenicity of 121 exonic LRRK2 variants in three ethnic series (Caucasian [N=12,590], Asian [N=2,338] and Arab-Berber [N=612]) consisting of 8,611 patients and 6,929 control subjects from 23 separate sites of the Genetic Epidemiology of Parkinson’s Disease Consortium.
Excluding carriers of previously known pathogenic mutations, new independent risk associations were found for polymorphic variants in Caucasian (p.M1646T, OR: 1.43, 95% CI: 1.15 – 1.78, P=0.0012) and Asian (p.A419V, OR: 2.27, 95% CI: 1.35 – 3.83, P=0.0011) populations. In addition, a protective haplotype was observed at >5% frequency (p.N551K-p.R1398H-p.K1423K) in the Caucasian and Asian series’, with a similar finding in the small Arab-Berber series that requires further study (combined 3-series OR: 0.82, 95% CI: 0.72 – 0.94, P=0.0043). Of the two previously reported Asian risk variants p.G2385R was found to be associated with disease (OR: 1.73, 95% CI: 1.20 – 2.49, P=0.0026) but no association was observed for p.R1628P (OR: 0.62, 95% CI: 0.36 – 1.07, P=0.087). Also in the Arab-Berber series, p.Y2189C showed potential evidence of risk association with PD (OR: 4.48, 95% CI: 1.33 – 15.09, P=0.012). Of note, two variants (p.I1371V and p.T2356I) which have been previously proposed as pathogenic were observed in patient and control subjects at the same frequency.
LRRK2 offers an example where multiple rare and common genetic variants in the same gene have independent effects on disease risk. Lrrk2, and the pathway in which it functions, is important in the etiology and pathogenesis of a greater proportion of patients with PD than previously believed.
The present study and original funding for the GEO-PD Consortium was supported by grants from Michael J. Fox Foundation. Studies at individual sites were supported by a number of funding agencies world-wide.
PMCID: PMC3208320  PMID: 21885347
Parkinson disease; LRRK2; genetics
5.  Modeling and Inferring Cleavage Patterns in Proliferating Epithelia 
PLoS Computational Biology  2009;5(6):e1000412.
The regulation of cleavage plane orientation is one of the key mechanisms driving epithelial morphogenesis. Still, many aspects of the relationship between local cleavage patterns and tissue-level properties remain poorly understood. Here we develop a topological model that simulates the dynamics of a 2D proliferating epithelium from generation to generation, enabling the exploration of a wide variety of biologically plausible cleavage patterns. We investigate a spectrum of models that incorporate the spatial impact of neighboring cells and the temporal influence of parent cells on the choice of cleavage plane. Our findings show that cleavage patterns generate “signature” equilibrium distributions of polygonal cell shapes. These signatures enable the inference of local cleavage parameters such as neighbor impact, maternal influence, and division symmetry from global observations of the distribution of cell shape. Applying these insights to the proliferating epithelia of five diverse organisms, we find that strong division symmetry and moderate neighbor/maternal influence are required to reproduce the predominance of hexagonal cells and low variability in cell shape seen empirically. Furthermore, we present two distinct cleavage pattern models, one stochastic and one deterministic, that can reproduce the empirical distribution of cell shapes. Although the proliferating epithelia of the five diverse organisms show a highly conserved cell shape distribution, there are multiple plausible cleavage patterns that can generate this distribution, and experimental evidence suggests that indeed plants and fruitflies use distinct division mechanisms.
Author Summary
Cell division is one of the key mechanisms driving organismal growth and morphogenesis. Yet many aspects of the relationship between local cell division (how a cell chooses an orientation to divide) and global tissue architecture (e.g., regular versus irregular cells) remain poorly understood. We present a computational framework for studying topological networks that are created by cell division; this framework reveals how certain tissue statistics can be used to infer properties of the cell division model. Recently it has been observed that five diverse organisms show almost identical cell shape distributions in their proliferating epithelial tissues, yet how this conservation arises is not understood. Using our model we show that the low variation observed in nature requires a strong correlation between how neighboring cells divide and that although the statistics of plants and fruitflies are almost identical, it is likely that they have evolved distinct cell division methods.
PMCID: PMC2688032  PMID: 19521504
7.  Potential early intermediates in anaerobic benzoate degradation by Rhodopseudomonas palustris. 
Alkali-treated extracts of Rhodopseudomonas palustris growing photosynthetically on benzoate were examined by gas chromatography/mass spectrometry for partially reduced benzoate derivatives. Two cyclic dienes, cyclohexa-2,5-diene-1-carboxylate and cyclohexa-1,4-diene-1-carboxylate, were detected. Either compound supported cell growth as effectively as benzoate. These results suggest that these cyclohexadienecarboxylates, probably as their coenzyme A esters, are the initial reduction products formed during anaerobic benzoate metabolism by R. palustris.
PMCID: PMC195304  PMID: 1610191
8.  Seatone in rheumatoid arthritis. 
Annals of the Rheumatic Diseases  1985;44(9):645-646.
PMCID: PMC1001730  PMID: 4037890
9.  Seatone in arthritis. 
PMCID: PMC1507599  PMID: 6797585
10.  Seatone in arthritis. 
PMCID: PMC1505733  PMID: 6786626
11.  An Encouraging Report * 
PMCID: PMC1830210  PMID: 13585296
12.  A Human Infection with Actinomyces Caprae 
British Medical Journal  1938;1(4028):612-614.
PMCID: PMC2086000  PMID: 20781325
13.  Vein Graft Preservation Solutions, Patency, and Outcomes After Coronary Artery Bypass Graft Surgery 
JAMA surgery  2014;149(8):798-805.
In vitro and animal model data suggest that intraoperative preservation solutions may influence endothelial function and vein graft failure (VGF) after coronary artery bypass graft (CABG) surgery. Clinical studies to validate these findings are lacking.
To evaluate the effect of vein graft preservation solutions on VGF and clinical outcomes in patients undergoing CABG surgery.
Data from the Project of Ex-Vivo Vein Graft Engineering via Transfection IV (PREVENT IV) study, a phase 3, multicenter, randomized, double-blind, placebo-controlled trial that enrolled 3014 patients at 107 US sites from August 1, 2002, through October 22, 2003, were used. Eligibility criteria for the trial included CABG surgery for coronary artery disease with at least 2 planned vein grafts.
Preservation of vein grafts in saline, blood, or buffered saline solutions.
One-year angiographic VGF and 5-year rates of death, myocardial infarction, and subsequent revascularization.
Most patients had grafts preserved in saline (1339 [44.4%]), followed by blood (971 [32.2%]) and buffered saline (507 [16.8%]). Baseline characteristics were similar among groups. One-year VGF rates were much lower in the buffered saline group than in the saline group (patient-level odds ratio [OR], 0.59 [95% CI, 0.45-0.78; P < .001]; graft-level OR, 0.63 [95% CI, 0.49-0.79; P < .001]) or the blood group (patient-level OR, 0.62 [95% CI, 0.46-0.83; P = .001]; graft-level OR, 0.63 [95% CI, 0.48-0.81; P < .001]). Use of buffered saline solution also tended to be associated with a lower 5-year risk for death, myocardial infarction, or subsequent revascularization compared with saline (hazard ratio, 0.81 [95% CI, 0.64-1.02; P = .08]) and blood (0.81 [0.63-1.03; P = .09]) solutions.
Patients undergoing CABG whose vein grafts were preserved in a buffered saline solution had lower VGF rates and trends toward better long-term clinical outcomes compared with patients whose grafts were preserved in saline- or blood-based solutions.
PMCID: PMC4332522  PMID: 25073921
14.  BET-bromodomain inhibition of MYC-amplified medulloblastoma 
MYC-amplified medulloblastomas are highly lethal tumors. BET bromodomain inhibition has recently been shown to suppress MYC-associated transcriptional activity in other cancers. The compound JQ1 inhibits BET bromodomain-containing proteins, including BRD4. Here we investigate BET bromodomain targeting for the treatment of MYC-amplified medulloblastoma.
Experimental Design
We evaluated the effects of genetic and pharmacological inhibition of BET bromodomains on proliferation, cell cycle, and apoptosis in established and newly generated patient- and GEMM-derived medulloblastoma cell lines and xenografts that harbored amplifications of MYC or MYCN. We also assessed the effect of JQ1 on MYC expression and global MYC-associated transcriptional activity. We assessed in vivo efficacy of JQ1 in orthotopic xenografts established in immunocompromised mice.
Treatment of MYC-amplified medulloblastoma cells with JQ1 decreased cell viability associated with arrest at G1 and apoptosis. We observed down-regulation of MYC expression and confirmed inhibition of MYC-associated transcriptional targets. Exogenous expression of MYC from a retroviral promoter reduced the effect of JQ1 on cell viability, suggesting that attenuated levels of MYC contribute to the functional effects of JQ1. JQ1 significantly prolonged survival of orthotopic xenograft models of MYC-amplified medulloblastoma (p<0.001). Xenografts harvested from mice after five doses of JQ1 had reduced expression of MYC mRNA and a reduced proliferative index.
JQ1 suppresses MYC expression and MYC-associated transcriptional activity in medulloblastomas, resulting in an overall decrease in medulloblastoma cell viability. These preclinical findings highlight the promise of BET bromodomain inhibitors as novel agents for MYC-amplified medulloblastoma.
PMCID: PMC4198154  PMID: 24297863
BET-bromodomain; JQ1; MYC; MYCN; MYCL1; medulloblastoma
15.  Prostate cancer 
Oncoimmunology  2014;3:e28049.
Vaccine-based immunotherapy can increase the overall survival of patients with advanced prostate cancer. However, the efficacy of vaccine-elicited anticancer immune responses is heavily influenced by the physical, nutritional, and psychological status of the patient. Given their importance, these parameters should be carefully considered for the design of future clinical trials testing this immunotherapeutic paradigm in prostate cancer patients.
PMCID: PMC4203569  PMID: 25340006
prostate; animal model; cancer vaccine; stress; microbiota; clinical trial
16.  Impact of Extracardiac Vascular Disease on Vein Graft Failure and Outcomes After Coronary Artery Bypass Surgery 
The Annals of thoracic surgery  2013;97(3):824-830.
While extracardiac vascular disease (ECVD), defined as a history of peripheral vascular disease (PVD) or cerebrovascular disease (CBVD), is common in patients undergoing coronary artery bypass graft (CABG) surgery, there are limited data available on the association between ECVD, vein graft failure (VGF), and clinical outcomes.
Using data from the Project of Ex-vivo Vein Graft Engineering via Transfection IV (PREVENTIV) trial (n = 3,014), 1-year angiographic follow-up and 5- year clinical outcomes (death, myocardial infarction, and revascularization) were determined in patients with and without ECVD. Logistic regression was used to assess risk of VGF. Generalized estimating equations methods were used to account for correlations in a graft level analysis. Kaplan-Meier estimates and Cox hazards regression were used to compare clinical outcomes. We similarly explored the association of the individual components CBVD and PVD with both VGF and clinical outcomes in an additive model.
Patients with ECVD (n=634, 21%) were older, more commonly female, and had more comorbidities, lower use of internal thoracic artery grafting, and overall worse graft quality than patients without ECVD. VGF rates tended to be higher (patient-level: odds ratio [OR]: 1.23, 95% confidence interval [CI] 0.96 to 1.58, p = 0.099; graft-level: OR: 1.23, 95% CI: 1.00 to 1.53, p = 0.053) in patients with ECVD. VGF rates were significantly higher among CBVD patients (OR: 1.42, 95% CI: 1.03 to 1.97, p = 0.035; graft-level: OR: 1.40, 95% CI: 1.06 to 1.85, p = 0.019). Patients with ECVD had a higher risk of death, myocardial infarction, or revascularization 5 years after CABG surgery (hazard ratio [HR]: 2.96, 95% CI: 2.02 to 4.35, p < 0.001). This relationship was driven by the subset of patients with PVD (HR = 3.32, 95% CI: 2.16 to 5.09, p < 0.001) and not by those with CBVD (HR = 1.10, 95% CI: 0.88 to 1.37, p = 0.40).
ECVD is common among patients undergoing CABG surgery and is associated with similar short-term but increasingly worse long-term clinical outcomes. This higher risk may be partly, but not exclusively, due to higher rates of VGF among these patients.
PMCID: PMC4324323  PMID: 24360877
17.  Relationship between postoperative clopidogrel use and subsequent angiographic and clinical outcomes following coronary artery bypass grafting 
Dual antiplatelet therapy with both aspirin and clopidogrel is increasingly used after coronary artery bypass grafting (CABG); however, little is known about the safety or efficacy. We sought to determine the relationship between postoperative clopidogrel and clinical and angiographic outcomes following CABG. We evaluated 3,014 patients from PREVENT IV who underwent CABG at 107 US sites. Postoperative antiplatelet therapy was left to physician discretion. Risk-adjusted angiographic and clinical outcomes were compared in patients taking and not taking clopidogrel 30 days post-CABG. At 30 days, 633 (21 %) patients were taking clopidogrel. Clopidogrel users were more likely to have peripheral vascular (15 vs. 11 %) and cerebrovascular disease (17 vs. 11 %), prior myocardial infarction (MI) (46 vs. 41 %), and off-pump surgery (33 vs. 18 %). Clopidogrel use was associated with statistically insignificant higher graft failure (adjusted odds ratio 1.3; 95 % confidence interval [CI] [1.0, 1.7]; P = 0.05). At 5-year follow-up, clopidogrel use was associated with similar composite rates of death, MI, or revascularization (27 vs. 24 %; adjusted hazard ratio 1.1; 95 % CI [0.9, 1.4]; P = 0.38) compared with those not using clopidogrel. There was an interaction between use of cardiopulmonary bypass and clopidogrel with a trend toward lower 5-year clinical events with clopidogrel in patients undergoing off-pump CABG. In this observational analysis, clopidogrel use was not associated with better 5-year outcomes following CABG. There may be better outcomes with clopidogrel among patients having off-pump surgery. Adequately powered randomized clinical trials are needed to determine the role of dual antiplatelet therapy after CABG.
PMCID: PMC4322756  PMID: 23543398
Clopidogrel; CABG; Dual antiplatelet therapy; Coronary artery bypass surgery; Outcomes
18.  Endoscopic Harvesting Device Type and Outcomes in Patients Undergoing Coronary Artery Bypass Surgery 
Annals of surgery  2014;260(2):402-408.
To evaluate angiographic and clinical outcomes associated with open and closed tunnel dissection endoscopic vein harvesting (EVH) devices.
Summary Background Data
A previous PREVENT-IV analysis reported that EVH for coronary artery bypass graft (CABG) surgery was associated with worse outcomes compared with traditional vein harvesting; however, outcomes by EVH device type were not available.
Using data from the PREVENT-IV trial, we compared 1549 patients from 75 surgical sites who underwent EVH with open (n=390) or closed (n=1159) harvest tunnel devices. Outcomes included the incidence of vein graft failure at 12 to 18 months and a composite of death, myocardial infarction, or revascularization through 5 years.
Among patients undergoing open and closed tunnel EVH, no difference in the per-patient incidence of vein graft failure (43.8% vs. 47.1%; adjusted odds ratio [OR], 0.91; 95% confidence interval [CI], 0.53 to 1.55; p=0.724) or per-graft incidence of vein graft failure (25.5% vs. 25.9%; adjusted OR, 0.96; 95% CI, 0.59 to 1.55; p=0.847) was observed. At 5 years, no difference was observed in the primary composite clinical outcome between open and closed system EVH patients (21.5% vs. 23.9%; adjusted hazard ratio, 0.85; 95% CI, 0.66 to 1.10; p=0.221).
No differences in angiographic or clinical outcomes were observed among patients who underwent open vs. closed tunnel endoscopic harvesting for coronary bypass surgery. These findings suggest that the risks associated with EVH that were reported in a previous PREVENT-IV analysis are not related to a specific EVH device.
PMCID: PMC4322758  PMID: 24368640
19.  The diagnostic dilemma of cerebellopontine angle lesions: re-evaluating your diagnosis 
BMJ Case Reports  2013;2013:bcr2012008358.
An unusual presentation of a life-threatening cerebellopontine abscess shows the importance of re-evaluating existing diagnoses when the clinical picture changes. Despite being rare, brain abscess is a potentially fatal condition that requires early radiological and surgical intervention. It has a varied presentation, with many cases showing no localising typical features, making it hard to diagnose at presentation. A high index of suspicion should be applied to cases exhibiting rapidly changing neurology. This is the first reported case of cerebellopontine abscess with no primary infective foci.
PMCID: PMC3603770  PMID: 23396935
20.  Accurate Identification of Deamidated Peptides in Global Proteomics using a Quadrupole Orbitrap Mass Spectrometer 
Journal of proteome research  2013;13(2):777-785.
Deamidation of asparagine and glutamine residues is a common post-translational modification. Researchers often rely on mass spectrometric based proteomic techniques for the identification of these post-translational sites. Mass spectral analysis of deamidated peptides is complicated and often misassigned due to overlapping 13C peak of the amidated form with the deamidated monoisotopic peak; these two peaks are only separated by 19.34 mDa. For proper assignment it is inherently important to use a mass spectrometer with high mass measurement accuracy and high resolving power. Herein, mouse brain tissue lysate was prepared using filter-aided sample preparation (FASP) method and Stage Tip fractionation followed by analysis on a nanoLC coupled to a quadrupole orbitrap (Q-Exactive) mass spectrometer to accurately identify more than 5400 proteins. Mass spectral data was processed using MASCOT and ProteoIQ for accurate identification of peptides and proteins. MASCOT search values for precursor and MS/MS mass tolerances were investigated, and it was determined data searched with greater than 5 ppm precursor mass tolerance resulted in the misassignment of deamidated peptides. Peptides that were identified with a mass measurement accuracy of ± 5 ppm were correctly assigned.
PMCID: PMC3976439  PMID: 24289162
21.  Using an electronic medical record (EMR) to conduct clinical trials: Salford Lung Study feasibility 
Real-world data on the benefit/risk profile of medicines is needed, particularly in patients who are ineligible for randomised controlled trials conducted for registration purposes. This paper describes the methodology and source data verification which enables the conduct of pre-licensing clinical trials of COPD and asthma in the community using the electronic medical record (EMR), NorthWest EHealth linked database (NWEH-LDB) and alert systems.
Dual verification of extracts into NWEH-LDB was performed using two independent data sources (Salford Integrated Record [SIR] and Apollo database) from one primary care practice in Salford (N = 3504). A feasibility study was conducted to test the reliability of the NWEH-LDB to support longitudinal data analysis and pragmatic clinical trials in asthma and COPD. This involved a retrospective extraction of data from all registered practices in Salford to identify a cohort of patients with a diagnosis of asthma (aged ≥18) and/or COPD (aged ≥40) and ≥2 prescriptions for inhaled bronchodilators during 2008. Health care resource utilisation (HRU) outcomes during 2009 were assessed. Exacerbations were defined as: prescription for oral corticosteroids (OCS) in asthma and prescription of OCS or antibiotics in COPD; and/or hospitalisation for a respiratory cause.
Dual verification demonstrated consistency between SIR and Apollo data sources: 3453 (98.6%) patients were common to both systems; 99.9% of prescription records were matched and of 29,830 diagnosis records, one record was missing from Apollo and 272 (0.9%) from SIR. Identified COPD patients were also highly concordant (Kappa coefficient = 0.98).
A total of 7981 asthma patients and 4478 COPD patients were identified within the NWEH-LDB. Cohort analyses enumerated the most commonly prescribed respiratory medication classes to be: inhaled corticosteroids (ICS) (42%) and ICS plus long-acting β2-agonist (LABA) (40%) in asthma; ICS plus LABA (55%) and long-acting muscarinic antagonists (36%) in COPD. During 2009 HRU was greater in the COPD versus asthma cohorts, and exacerbation rates in 2009 were higher in patients who had ≥2 exacerbations versus ≤1 exacerbation in 2008 for both asthma (137.5 vs. 20.3 per 100 person-years, respectively) and COPD (144.6 vs. 41.0, respectively).
Apollo and SIR data extracts into NWEH-LDB showed a high level of concordance for asthma and COPD patients. Longitudinal data analysis characterized the COPD and asthma populations in Salford including medications prescribed and health care utilisation outcomes suitable for clinical trial planning.
PMCID: PMC4331140
Asthma; COPD; Electronic medical record; EMR; Real-world data; Primary and secondary healthcare; Dual verification
22.  Evaluation of prenylated peptides for use in cellular imaging and biochemical analysis. 
Protein prenylation involves the addition of a farnesyl (C15) or geranylgeranyl (C20) isoprenoid moiety onto the C-terminus of approximately 2% of all mammalian proteins. This hydrophobic modification serves to direct membrane association of the protein. Due to the finding that the oncogenic protein Ras is naturally prenylated, several researchers have developed inhibitors of the prenyltransferase enzymes as cancer therapeutics. Despite numerous studies on the enzymology of prenylation in vitro, many questions remain about the process of prenylation in living cells. Using a combination of flow cytometry and confocal microscopy, we have shown that synthetic fluorescently-labeled prenylated peptides enter a variety of different cell types. Additionally, using capillary electrophoresis we have shown that these peptides can be detected in minute quantities from lysates of cells treated with these peptides. This method will allow for further study of the enzymology of protein prenylation in living cells.
PMCID: PMC4318554  PMID: 24146406
Peptide; lipid modification; post-translational modification; prenylation; farnesyl; cell-penetrating peptide
23.  Flurpiridaz F 18 PET: Phase II Safety and Clinical Comparison with SPECT Myocardial Perfusion Imaging for Detection of Coronary Artery Disease 
Phase II trial to assess flurpiridaz F 18 for safety and compare its diagnostic performance for PET myocardial perfusion imaging (MPI) to Tc-99m SPECT-MPI regarding image quality, interpretative certainty, defect magnitude and detection of coronary artery disease (CAD)(≥ 50% stenosis) on invasive coronary angiography (ICA).
In preclinical and phase I studies, flurpiridaz F 18 has shown characteristics of an essentially ideal MPI tracer.
143 patients from 21 centers underwent rest-stress PET and Tc-99m SPECT-MPI. Eighty-six patients underwent ICA, and 39 had low-likelihood of CAD. Images were scored by 3 independent, blinded readers.
A higher % of images were rated as excellent/good on PET vs. SPECT on stress (99.2% vs. 88.5%, p<0.01) and rest (96.9% vs. 66.4, p<0.01) images. Diagnostic certainty of interpretation (% cases with definitely abnormal/normal interpretation) was higher for PET vs. SPECT (90.8% vs. 70.9%, p<0.01). In 86 patients who underwent ICA, sensitivity of PET was higher than SPECT [78.8% vs. 61.5%, respectively (p=0.02)]. Specificity was not significantly different (PET:76.5% vs. SPECT:73.5%). Receiver operating characteristic curve area was 0.82±0.05 for PET and 0.70±0.06 for SPECT (p=0.04). Normalcy rate was 89.7% with PET and 97.4% with SPECT (p=NS). In patients with CAD on ICA, the magnitude of reversible defects was greater with PET than SPECT (p=0.008). Extensive safety assessment revealed that flurpiridaz F 18 was safe in this cohort.
In this Phase 2 trial, PET MPI using flurpiridaz F 18 was safe and superior to SPECT MPI for image quality, interpretative certainty, and overall CAD diagnosis.
PMCID: PMC4316725  PMID: 23265345
Flurpiridaz F18; Myocarial Perfusion; SPECT
25.  Researcher Perceptions of Ethical Guidelines and Codes of Conduct 
Accountability in research  2015;22(3):123-138.
Ethical codes of conduct exist in almost every profession. Field-specific codes of conduct have been around for decades, each articulating specific ethical and professional guidelines. However, there has been little empirical research on researchers’ perceptions of these codes of conduct. In the present study, we interviewed faculty members in six research disciplines and identified five themes bearing on the circumstances under which they use ethical guidelines and the underlying reasons for not adhering to such guidelines. We then identify problems with the manner in which codes of conduct in academia are constructed and offer solutions for overcoming these problems.
PMCID: PMC4313573  PMID: 25635845
guidelines; ethics; misconduct; codes of conduct

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