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- Hillier, Ladeana W, et al.
(författare)
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Sequence and comparative analysis of the chicken genome provide unique perspectives on vertebrate evolution
- 2004
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Ingår i: Nature. - 0028-0836 .- 1476-4687. ; 432:7018, s. 695-716
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Tidskriftsartikel (refereegranskat)abstract
- We present here a draft genome sequence of the red jungle fowl, Gallus gallus. Because the chicken is a modern descendant of the dinosaurs and the first non-mammalian amniote to have its genome sequenced, the draft sequence of its genome--composed of approximately one billion base pairs of sequence and an estimated 20,000-23,000 genes--provides a new perspective on vertebrate genome evolution, while also improving the annotation of mammalian genomes. For example, the evolutionary distance between chicken and human provides high specificity in detecting functional elements, both non-coding and coding. Notably, many conserved non-coding sequences are far from genes and cannot be assigned to defined functional classes. In coding regions the evolutionary dynamics of protein domains and orthologous groups illustrate processes that distinguish the lineages leading to birds and mammals. The distinctive properties of avian microchromosomes, together with the inferred patterns of conserved synteny, provide additional insights into vertebrate chromosome architecture.
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- Jayson, Gordon, et al.
(författare)
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Molecular imaging and biological evaluation of HuMV833 anti-VEGF antibody : Implications for trial design of antiangiogenic antibodies
- 2002
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Ingår i: Journal of the National Cancer Institute. - 0027-8874 .- 1460-2105. ; 94:19, s. 1484-1493
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Tidskriftsartikel (refereegranskat)abstract
- Background: Vascular endothelial growth factor (VEGF) is a potent angiogenic cytokine, and various inhibitory agents, including specific antibodies, have been developed to block VEGF-stimulated angiogenesis. We developed HuMV833, a humanized version of a mouse monoclonal anti-VEGF antibody (MV833) that has antitumor activity against a number of human tumor xenografts, and investigated the distribution and biologic effects of HuMV833 in patients in a phase I trial. Methods: Twenty patients with progressive solid tumors were treated with various doses of HuMV833 0.3, 1, 3, or 10 mg/kg). Positron emission tomography with 124I-HuMV833 was used to measure the antibody distribution in and clearance from tissues. Magnetic resonance imaging was used to measure the vascular permeability surface area product with a first-pass pharmacokinetic model (Kfp) to determine tumor vascular permeability. Results: The antibody was generally well tolerated, although the incremental dose, phase I study design, and pharmacodynamic end-points could not identify the optimum biologically active dose. Antibody distribution and clearance were markedly heterogeneous between and within patients and between and within individual tumor. HuMV833 distribution to normal tissues also varied among patients, but the antibody was cleared from these tissues in a homogeneous fashion. Permeability was strongly heterogeneous between and within patients and between and within individual tumors. All tumors showed a reduction in kfp 48 hours after the first treatment (median = 44%, range = 4%-91%). Conclusions: Because of the heterogeneity in tumor biology with respect to anti-body uptake and clearance, we suggest that either intrapatient dose escalation approaches or larger, more precisely defined patient cohorts would be preferable to conventional strategies in the design of phase I studies with anitiangiogenic compounds like HuMV833.
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