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1.
J Exp Biol ; 216(Pt 8): 1458-69, 2013 Apr 15.
Article in English | MEDLINE | ID: mdl-23264488

ABSTRACT

Oyster larvae (Crassostrea virginica) could enhance their settlement success by moving toward the seafloor in the strong turbulence associated with coastal habitats. We characterized the behavior of individual oyster larvae in grid-generated turbulence by measuring larval velocities and flow velocities simultaneously using infrared particle image velocimetry. We estimated larval behavioral velocities and propulsive forces as functions of the kinetic energy dissipation rate ε, strain rate γ, vorticity ξ and acceleration α. In calm water most larvae had near-zero vertical velocities despite propelling themselves upward (swimming). In stronger turbulence all larvae used more propulsive force, but relative to the larval axis, larvae propelled themselves downward (diving) instead of upward more frequently and more forcefully. Vertical velocity magnitudes of both swimmers and divers increased with turbulence, but the swimming velocity leveled off as larvae were rotated away from their stable, velum-up orientation in strong turbulence. Diving speeds rose steadily with turbulence intensity to several times the terminal fall velocity in still water. Rapid dives may require a switch from ciliary swimming to another propulsive mode such as flapping the velum, which would become energetically efficient at the intermediate Reynolds numbers attained by larvae in strong turbulence. We expected larvae to respond to spatial or temporal velocity gradients, but although the diving frequency changed abruptly at a threshold acceleration, the variation in propulsive force and behavioral velocity was best explained by the dissipation rate. Downward propulsion could enhance oyster larval settlement by raising the probability of larval contact with oyster reef patches.


Subject(s)
Ostreidae/physiology , Algorithms , Animals , Larva/physiology , Rheology , Swimming
2.
Cancer Res ; 68(6): 1935-44, 2008 Mar 15.
Article in English | MEDLINE | ID: mdl-18339875

ABSTRACT

Cancer cells are characterized by the ability to grow in an anchorage-independent manner. The activity of the nonreceptor tyrosine kinase, focal adhesion kinase (FAK), is thought to contribute to this phenotype. FAK localizes in focal adhesion plaques and has a role as a scaffolding and signaling protein for other adhesion molecules. Recent studies show a strong correlation between increased FAK expression and phosphorylation status and the invasive phenotype of aggressive human tumors. PF-562,271 is a potent, ATP-competitive, reversible inhibitor of FAK and Pyk2 catalytic activity with a IC(50) of 1.5 and 14 nmol/L, respectively. Additionally, PF-562,271 displayed robust inhibition in an inducible cell-based assay measuring phospho-FAK with an IC(50) of 5 nmol/L. PF-562,271 was evaluated against multiple kinases and displays >100x selectivity against a long list of nontarget kinases. PF-562,271 inhibits FAK phosphorylation in vivo in a dose-dependent fashion (calculated EC(50) of 93 ng/mL, total) after p.o. administration to tumor-bearing mice. In vivo inhibition of FAK phosphorylation (>50%) was sustained for >4 hours with a single p.o. dose of 33 mg/kg. Antitumor efficacy and regressions were observed in multiple human s.c. xenograft models. No weight loss, morbidity, or mortality were observed in any in vivo experiment. Tumor growth inhibition was dose and drug exposure dependent. Taken together, these data show that kinase inhibition with an ATP-competitive small molecule inhibitor of FAK decreases the phospho-status in vivo, resulting in robust antitumor activity.


Subject(s)
Focal Adhesion Protein-Tyrosine Kinases/antagonists & inhibitors , Glioblastoma/drug therapy , Indoles/pharmacology , Protein Kinase Inhibitors/pharmacology , Sulfonamides/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Cell Line, Tumor , Female , Glioblastoma/enzymology , Glioblastoma/pathology , Humans , Indoles/chemical synthesis , Indoles/chemistry , Mice , Mice, Nude , Models, Chemical , Phosphorylation/drug effects , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Sulfonamides/chemical synthesis , Sulfonamides/chemistry , Xenograft Model Antitumor Assays
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