Overexpression of MMPs in Corneas Requiring Penetrating and Deep Anterior Lamellar Keratoplasty.

PurposeMatrix metalloproteinases (MMPs) comprise a family of zinc-dependent endopeptidases involved in wound healing processes, including neovascularization and fibrosis. We assessed MMP protein expression levels in diseased corneas of patients requiring penetrating and deep anterior lamellar keratoplasty. The purpose of this study was to test the hypothesis that upregulation of MMPs in diseased corneas is positively associated with clinical levels of corneal neovascularization and fibrosis.MethodsProtein expression levels of nine individual MMPs were quantified simultaneously in human corneal lysates by using the Bio-Plex Pro Human MMP 9-Plex Panel and the MAGPIX technology. Measurements of MMP1, MMP2, MMP3, MMP7, MMP8, MMP9, MMP10, MMP12, and MMP13 were performed on diseased specimens from 21 patients undergoing corneal transplantation (17 for penetrating keratoplasty and 4 for deep anterior lamellar keratoplasty) and 6 normal control corneas.ResultsLuminex-based expression analysis revealed a significant overexpression of four of the nine MMPs tested (MMP2, MMP8, MMP12, and MMP13) in patient samples compared to control. Significant overexpression of MMP1, MMP2, MMP8, MMP12, and MMP13 was observed in diseased corneas with neovascularization compared with diseased corneas without neovascularization. Overexpression of MMP1, MMP2, MMP8, MMP12, and MMP13 also corresponded with the levels of corneal fibrosis. Finally, reduced expression of MMP3 was detected in keratoconus patients.ConclusionsMultiple MMPs are expressed in the corneas of patients with chronic disease requiring keratoplasty even when the pathologic process appears to be clinically inactive. In particular, the expression of several MMPs (MMP2, MMP8, MMP12, and MMP13) is positively associated with increased levels corneal fibrosis and neovascularization

Metastatic Melanomas Express Inhibitory Low Affinity Fc Gamma Receptor and Escape Humoral Immunity

Our research, inspired by the pioneering works of Isaac Witz in the 1980s, established that 40% of human metastatic melanomas express ectopically inhibitory Fc gamma receptors (FcγRIIB), while they are detected on less than 5% of primary cutaneous melanoma and not on melanocytes. We demonstrated that these tumoral FcγRIIB act as decoy receptors that bind the Fc portion of antimelanoma IgG, which may prevent Fc recognition by the effector cells of the immune system and allow the metastatic melanoma to escape the humoral/natural immune response. The FcγRIIB is able to inhibit the ADCC (antibody dependent cell cytotoxicity) in vitro. Interestingly, the percentage of melanoma expressing the FcγRIIB is high (70%) in organs like the liver, which is rich in patrolling NK (natural killer) cells that exercise their antitumoral activity by ADCC. We found that this tumoral FcγRIIB is fully functional and that its inhibitory potential can be triggered depending on the specificity of the anti-tumor antibody with which it interacts. Together these observations elucidate how metastatic melanomas interact with and potentially evade humoral immunity and provide direction for the improvement of anti-melanoma monoclonal antibody therapy

An Explanation for the Observed Weak Size Evolution of Disk Galaxies

Surveys of distant galaxies with the Hubble Space Telescope and from the ground have shown that there is only mild evolution in the relationship between radial size and stellar mass for galactic disks from z~1 to the present day. Using a sample of nearby disk-dominated galaxies from the Sloan Digital Sky Survey (SDSS), and high redshift data from the GEMS (Galaxy Evolution from Morphology and SEDs) survey, we investigate whether this result is consistent with theoretical expectations within the hierarchical paradigm of structure formation. The relationship between virial radius and mass for dark matter halos in the LCDM model evolves by about a factor of two over this interval. However, N-body simulations have shown that halos of a given mass have less centrally concentrated mass profiles at high redshift. When we compute the expected disk size-stellar mass distribution, accounting for this evolution in the internal structure of dark matter halos and the adiabatic contraction of the dark matter by the self-gravity of the collapsing baryons, we find that the predicted evolution in the mean size at fixed stellar mass since z~1 is about 15-20 percent, in good agreement with the observational constraints from GEMS. At redshift z~2, the model predicts that disks at fixed stellar mass were on average only 60% as large as they are today. Similarly, we predict that the rotation velocity at a given stellar mass (essentially the zero-point of the Tully-Fisher relation) is only about 10 percent larger at z~1 (20 percent at z~2) than at the present day.Comment: 13 pages, 6 figures, accepted for publication in ApJ. Revised in response to referee's comments to improve clariry. Results are unchange

GEMS: Galaxy fitting catalogues and testing parametric galaxy fitting codes

In the context of measuring structure and morphology of intermediate redshift galaxies with recent HST/ACS surveys, we tune, test, and compare two widely used fitting codes (GALFIT and GIM2D) for fitting single-component Sersic models to the light profiles of both simulated and real galaxy data. We find that fitting accuracy depends sensitively on galaxy profile shape. Exponential disks are well fit with Sersic models and have small measurement errors, whereas fits to de Vaucouleurs profiles show larger uncertainties owing to the large amount of light at large radii. We find that both codes provide reliable fits and little systematic error, when the effective surface brightness is above that of the sky. Moreover, both codes return errors that significantly underestimate the true fitting uncertainties, which are best estimated with simulations. We find that GIM2D suffers significant systematic errors for spheroids with close companions owing to the difficulty of effectively masking out neighboring galaxy light; there appears to be no work around to this important systematic in GIM2D's current implementation. While this crowding error affects only a small fraction of galaxies in GEMS, it must be accounted for in the analysis of deeper cosmological images or of more crowded fields with GIM2D. In contrast, GALFIT results are robust to the presence of neighbors because it can simultaneously fit the profiles of multiple companions thereby deblending their effect on the fit to the galaxy of interest. We find GALFIT's robustness to nearby companions and factor of >~20 faster runtime speed are important advantages over GIM2D for analyzing large HST/ACS datasets. Finally we include our final catalog of fit results for all 41,495 objects detected in GEMS.Comment: Accepted for publication in ApJS October 2007, v172n2; 25 pages, 16 Figures, 9 Tables; for hi-resolution version, see http://www.mpia.de/homes/bhaeussl/galaxy_fitting.pdf. For results, catalogues and files for code-testing, see http://www.mpia.de/GEMS/fitting_paper.htm

Training of Instrumentalists and Development of New Technologies on SOFIA

This white paper is submitted to the Astronomy and Astrophysics 2010 Decadal Survey (Astro2010)1 Committee on the State of the Profession to emphasize the potential of the Stratospheric Observatory for Infrared Astronomy (SOFIA) to contribute to the training of instrumentalists and observers, and to related technology developments. This potential goes beyond the primary mission of SOFIA, which is to carry out unique, high priority astronomical research. SOFIA is a Boeing 747SP aircraft with a 2.5 meter telescope. It will enable astronomical observations anywhere, any time, and at most wavelengths between 0.3 microns and 1.6 mm not accessible from ground-based observatories. These attributes, accruing from the mobility and flight altitude of SOFIA, guarantee a wealth of scientific return. Its instrument teams (nine in the first generation) and guest investigators will do suborbital astronomy in a shirt-sleeve environment. The project will invest $10M per year in science instrument development over a lifetime of 20 years. This, frequent flight opportunities, and operation that enables rapid changes of science instruments and hands-on in-flight access to the instruments, assure a unique and extensive potential - both for training young instrumentalists and for encouraging and deploying nascent technologies. Novel instruments covering optical, infrared, and submillimeter bands can be developed for and tested on SOFIA by their developers (including apprentices) for their own observations and for those of guest observers, to validate technologies and maximize observational effectiveness.Comment: 10 pages, no figures, White Paper for Astro 2010 Survey Committee on State of the Professio

The eMERGE Network: A consortium of biorepositories linked to electronic medical records data for conducting genomic studies

<p>Abstract</p> <p>Introduction</p> <p>The eMERGE (electronic MEdical Records and GEnomics) Network is an NHGRI-supported consortium of five institutions to explore the utility of DNA repositories coupled to Electronic Medical Record (EMR) systems for advancing discovery in genome science. eMERGE also includes a special emphasis on the ethical, legal and social issues related to these endeavors.</p> <p>Organization</p> <p>The five sites are supported by an Administrative Coordinating Center. Setting of network goals is initiated by working groups: (1) Genomics, (2) Informatics, and (3) Consent & Community Consultation, which also includes active participation by investigators outside the eMERGE funded sites, and (4) Return of Results Oversight Committee. The Steering Committee, comprised of site PIs and representatives and NHGRI staff, meet three times per year, once per year with the External Scientific Panel.</p> <p>Current progress</p> <p>The primary site-specific phenotypes for which samples have undergone genome-wide association study (GWAS) genotyping are cataract and HDL, dementia, electrocardiographic QRS duration, peripheral arterial disease, and type 2 diabetes. A GWAS is also being undertaken for resistant hypertension in ≈2,000 additional samples identified across the network sites, to be added to data available for samples already genotyped. Funded by ARRA supplements, secondary phenotypes have been added at all sites to leverage the genotyping data, and hypothyroidism is being analyzed as a cross-network phenotype. Results are being posted in dbGaP. Other key eMERGE activities include evaluation of the issues associated with cross-site deployment of common algorithms to identify cases and controls in EMRs, data privacy of genomic and clinically-derived data, developing approaches for large-scale meta-analysis of GWAS data across five sites, and a community consultation and consent initiative at each site.</p> <p>Future activities</p> <p>Plans are underway to expand the network in diversity of populations and incorporation of GWAS findings into clinical care.</p> <p>Summary</p> <p>By combining advanced clinical informatics, genome science, and community consultation, eMERGE represents a first step in the development of data-driven approaches to incorporate genomic information into routine healthcare delivery.</p

Speech Communication

Contains research objectives and summary of research on six research projects and reports on three research projects.National Institutes of Health (Grant 5 RO1 NS04332-13)National Institutes of Health (Fellowship 1 F22 MH5825-01)National Institutes of Health (Grant 1 T32 NS07040-01)National Institutes of Health (Fellowship 1 F22 NS007960)National Institutes of Health (Fellowship 1 F22 HD019120)National Institutes of Health (Fellowship 1 F22 HD01919-01)U. S. Army (Contract DAAB03-75-C-0489)National Institutes of Health (Grant 5 RO1 NS04332-12

DNA methylation-based classification of central nervous system tumours.

Accurate pathological diagnosis is crucial for optimal management of patients with cancer. For the approximately 100 known tumour types of the central nervous system, standardization of the diagnostic process has been shown to be particularly challenging-with substantial inter-observer variability in the histopathological diagnosis of many tumour types. Here we present a comprehensive approach for the DNA methylation-based classification of central nervous system tumours across all entities and age groups, and demonstrate its application in a routine diagnostic setting. We show that the availability of this method may have a substantial impact on diagnostic precision compared to standard methods, resulting in a change of diagnosis in up to 12% of prospective cases. For broader accessibility, we have designed a free online classifier tool, the use of which does not require any additional onsite data processing. Our results provide a blueprint for the generation of machine-learning-based tumour classifiers across other cancer entities, with the potential to fundamentally transform tumour pathology

Electronic medical records and genomics (eMERGE) network exploration in cataract: Several new potential susceptibility loci

Purpose Cataract is the leading cause of blindness in the world, and in the United States accounts for approximately 60% of Medicare costs related to vision. The purpose of this study was to identify genetic markers for age-related cataract through a genome-wide association study (GWAS). Methods: In the electronic medical records and genomics (eMERGE) network, we ran an electronic phenotyping algorithm on individuals in each of five sites with electronic medical records linked to DNA biobanks. We performed a GWAS using 530,101 SNPs from the Illumina 660W-Quad in a total of 7,397 individuals (5,503 cases and 1,894 controls). We also performed an age-at-diagnosis case-only analysis. Results: We identified several statistically significant associations with age-related cataract (45 SNPs) as well as age at diagnosis (44 SNPs). The 45 SNPs associated with cataract at p<1×10−5 are in several interesting genes, including ALDOB, MAP3K1, and MEF2C. All have potential biologic relationships with cataracts. Conclusions: This is the first genome-wide association study of age-related cataract, and several regions of interest have been identified. The eMERGE network has pioneered the exploration of genomic associations in biobanks linked to electronic health records, and this study is another example of the utility of such resources. Explorations of age-related cataract including validation and replication of the association results identified herein are needed in future studies