| 1. |
- Jayson, Gordon, et al.
(författare)
-
Molecular imaging and biological evaluation of HuMV833 anti-VEGF antibody : Implications for trial design of antiangiogenic antibodies
- 2002
-
Ingår i: Journal of the National Cancer Institute. - 0027-8874 .- 1460-2105. ; 94:19, s. 1484-1493
-
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.
|
|
| 2. |
- Luo, Yiqi, et al.
(författare)
-
Transient dynamics of terrestrial carbon storage : Mathematical foundation and its applications
- 2017
-
Ingår i: Biogeosciences. - : Copernicus GmbH. - 1726-4170 .- 1726-4189. ; 14:1, s. 145-161
-
Tidskriftsartikel (refereegranskat)abstract
- Terrestrial ecosystems have absorbed roughly 30 % of anthropogenic CO2 emissions over the past decades, but it is unclear whether this carbon (C) sink will endure into the future. Despite extensive modeling and experimental and observational studies, what fundamentally determines transient dynamics of terrestrial C storage under global change is still not very clear. Here we develop a new framework for understanding transient dynamics of terrestrial C storage through mathematical analysis and numerical experiments. Our analysis indicates that the ultimate force driving ecosystem C storage change is the C storage capacity, which is jointly determined by ecosystem C input (e.g., net primary production, NPP) and residence time. Since both C input and residence time vary with time, the C storage capacity is time-dependent and acts as a moving attractor that actual C storage chases. The rate of change in C storage is proportional to the C storage potential, which is the difference between the current storage and the storage capacity. The C storage capacity represents instantaneous responses of the land C cycle to external forcing, whereas the C storage potential represents the internal capability of the land C cycle to influence the C change trajectory in the next time step. The influence happens through redistribution of net C pool changes in a network of pools with different residence times. Moreover, this and our other studies have demonstrated that one matrix equation can replicate simulations of most land C cycle models (i.e., physical emulators). As a result, simulation outputs of those models can be placed into a three-dimensional (3-D) parameter space to measure their differences. The latter can be decomposed into traceable components to track the origins of model uncertainty. In addition, the physical emulators make data assimilation computationally feasible so that both C flux-and pool-related datasets can be used to better constrain model predictions of land C sequestration. Overall, this new mathematical framework offers new approaches to understanding, evaluating, diagnosing, and improving land C cycle models.
|
|
| 3. |
- Ripa, Jörgen, et al.
(författare)
-
Stochasticity, Environmental
- 2012. - 1
-
Ingår i: Encyclopedia of Theoretical Ecology. - 9780520269651 ; :4, s. 712-717
-
Bokkapitel (övrigt vetenskapligt/konstnärligt)
|
|
