Dataset Information

The PUWMa (Pfizer-funded study from the University of California Los Angeles (UCLA), Washington University (WASH-U), and Massachusetts General Hospital (MGH)) GWAS of ADHD

ABSTRACT:

The PUWMa GWAS of ADHD is a multi-site collaboration initiated to conduct a family-based association study from existing research samples. The source sample of ADHD families was ascertained at Massachusetts General Hospital (MGH, N=309 trios), Washington University at St. Louis (WASH-U, N=272 trios), and University of California at Los Angeles (UCLA, N=156 trios). All offspring met criteria for DSM-IV-TR attention-deficit hyperactivity disorder with childhood onset.

PROVIDER: phs000358.v1.p1 | EGA |

REPOSITORIES: EGA

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Publications

Meta-analysis of genome-wide association studies of attention-deficit/hyperactivity disorder.

Neale Benjamin M BM Medland Sarah E SE Ripke Stephan S Asherson Philip P Franke Barbara B Lesch Klaus-Peter KP Faraone Stephen V SV Nguyen Thuy Trang TT Schäfer Helmut H Holmans Peter P Daly Mark M Steinhausen Hans-Christoph HC Freitag Christine C Reif Andreas A Renner Tobias J TJ Romanos Marcel M Romanos Jasmin J Walitza Susanne S Warnke Andreas A Meyer Jobst J Palmason Haukur H Buitelaar Jan J Vasquez Alejandro Arias AA Lambregts-Rommelse Nanda N Gill Michael M Anney Richard J L RJ Langely Kate K O'Donovan Michael M Williams Nigel N Owen Michael M Thapar Anita A Kent Lindsey L Sergeant Joseph J Roeyers Herbert H Mick Eric E Biederman Joseph J Doyle Alysa A Smalley Susan S Loo Sandra S Hakonarson Hakon H Elia Josephine J Todorov Alexandre A Miranda Ana A Mulas Fernando F Ebstein Richard P RP Rothenberger Aribert A Banaschewski Tobias T Oades Robert D RD Sonuga-Barke Edmund E McGough James J Nisenbaum Laura L Middleton Frank F Hu Xiaolan X Nelson Stan S

Journal of the American Academy of Child and Adolescent Psychiatry 20100801 9

<h4>Objective</h4>Although twin and family studies have shown attention-deficit/hyperactivity disorder (ADHD) to be highly heritable, genetic variants influencing the trait at a genome-wide significant level have yet to be identified. As prior genome-wide association studies (GWAS) have not yielded significant results, we conducted a meta-analysis of existing studies to boost statistical power.<h4>Method</h4>We used data from four projects: a) the Children's Hospital of Philadelphia (CHOP); b) p ...[more]

PMID: 20732625

Publication: 1/2

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Project description:Mathematical modeling of mutant transferrin-CRM107 molecular conjugates for cancer therapy. Yoon DJ1, Chen KY1, Lopes AM1, Pan AA1, Shiloach J2, Mason AB3, Kamei DT4. Author information 1 Department of Bioengineering, University of California, Los Angeles, 420 Westwood Plaza, 5121 Engineering V, Los Angeles, CA 90095, USA. 2 Biotechnology Core Laboratory, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Health, Bethesda, MD 20892, USA. 3 Department of Biochemistry, University of Vermont College of Medicine, Burlington, VT 05405, USA. 4 Department of Bioengineering, University of California, Los Angeles, 420 Westwood Plaza, 5121 Engineering V, Los Angeles, CA 90095, USA. Electronic address: kamei@seas.ucla.edu. Abstract The transferrin (Tf) trafficking pathway is a promising mechanism for use in targeted cancer therapy due to the overexpression of transferrin receptors (TfRs) on cancerous cells. We have previously developed a mathematical model of the Tf/TfR trafficking pathway to improve the efficiency of Tf as a drug carrier. By using diphtheria toxin (DT) as a model toxin, we found that mutating the Tf protein to change its iron release rate improves cellular association and efficacy of the drug. Though this is an improvement upon using wild-type Tf as the targeting ligand, conjugated toxins like DT are unfortunately still highly cytotoxic at off-target sites. In this work, we address this hurdle in cancer research by developing a mathematical model to predict the efficacy and selectivity of Tf conjugates that use an alternative toxin. For this purpose, we have chosen to study a mutant of DT, cross-reacting material 107 (CRM107). First, we developed a mathematical model of the Tf-DT trafficking pathway by extending our Tf/TfR model to include intracellular trafficking via DT and DT receptors. Using this mathematical model, we subsequently investigated the efficacy of several conjugates in cancer cells: DT and CRM107 conjugated to wild-type Tf, as well as to our engineered mutant Tf proteins (K206E/R632A Tf and K206E/R534A Tf). We also investigated the selectivity of mutant Tf-CRM107 against non-neoplastic cells. Through the use of our mathematical model, we predicted that (i) mutant Tf-CRM107 exhibits a greater cytotoxicity than wild-type Tf-CRM107 against cancerous cells, (ii) this improvement was more drastic with CRM107 conjugates than with DT conjugates, and (iii) mutant Tf-CRM107 conjugates were selective against non-neoplastic cells. These predictions were validated with in vitro cytotoxicity experiments, demonstrating that mutant Tf-CRM107 conjugates is indeed a more suitable therapeutic agent. Validation from in vitro experiments also confirmed that such whole-cell kinetic models can be useful in cancer therapeutic design. Copyright © 2017 Elsevier Ltd. All rights reserved.

Dataset Information

The PUWMa (Pfizer-funded study from the University of California Los Angeles (UCLA), Washington University (WASH-U), and Massachusetts General Hospital (MGH)) GWAS of ADHD

Publications

Meta-analysis of genome-wide association studies of attention-deficit/hyperactivity disorder.

Similar Datasets

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