Background-Pharmacogenetic-guided dosing of warfarin is a promising application of "personalized medicine" but has not been adequately tested in randomized trials. Methods and Results-Consenting patients (nϭ206) being initiated on warfarin were randomized to pharmacogeneticguided or standard dosing. Buccal swab DNA was genotyped for CYP2C9 *2 and CYP2C9 *3 and VKORC1 C1173T with a rapid assay. Standard dosing followed an empirical protocol, whereas pharmacogenetic-guided dosing followed a regression equation including the 3 genetic variants and age, sex, and weight.

AG14361 is, to our knowledge, the first high-potency PARP-1 inhibitor with the specificity and in vivo activity to enhance chemotherapy and radiation therapy of human cancer.

The ligand-binding head region of integrin ␤ subunits contains a von Willebrand factor type A domain (␤A). Ligand binding activity is regulated through conformational changes in ␤A, and ligand recognition also causes conformational changes that are transduced from this domain. The molecular basis of signal transduction to and from ␤A is uncertain. The epitopes of mAbs 15/7 and HUTS-4 lie in the ␤ 1 subunit hybrid domain, which is connected to the lower face of ␤A. Changes in the expression of these epitopes are induced by conformational changes in ␤A caused by divalent cations, function perturbing mAbs, or ligand recognition. Recombinant truncated ␣ 5 ␤ 1 with a mutation L358A in the ␣7 helix of ␤A has constitutively high expression of the 15/7 and HUTS-4 epitopes, mimics the conformation of the ligand-occupied receptor, and has high constitutive ligand binding activity. The epitopes of 15/7 and HUTS-4 map to a region of the hybrid domain that lies close to an interface with the ␣ subunit. Taken together, these data suggest that the transduction of conformational changes through ␤A involves shape shifting in the ␣7 helix region, which is linked to a swing of the hybrid domain away from the ␣ subunit.Integrins mediate a wide variety of essential cell-matrix and cell-cell interactions and also participate in many common disease processes (1, 2). Integrins are heterodimers containing non-covalently associated ␣ and ␤ subunits; each subunit has a large extracellular domain linked to a transmembrane segment and a short cytoplasmic tail. Integrins participate in bi-directional signaling; ligand recognition is dynamically regulated by "inside-out" signaling, and ligand occupancy leads to "outsidein" signals that affect cell migration, growth, differentiation, and survival (3-5). Modulation of integrin activity is essential in such processes as leukocyte migration to sites of tissue injury and the aggregation of platelets to form a hemostatic plug. Integrin activation can be mimicked in vitro by divalent cations such as Mn 2ϩ or Mg 2ϩ (6). Three major conformational states of integrins can be distinguished using monoclonal antibodies (mAbs) 1 : an inactive (resting or low affinity) state, an active (or high affinity) state, and a ligand-occupied state (7). The conformations of the inactive and active states are discriminated by low and high expression, respectively, of activation epitopes (such as those recognized by 12G10, 15/7, and 9EG7 for the ␤ 1 subunit, see Refs. 8 -10). The ligand-occupied conformer expresses high levels of ligand-induced binding site (LIBS) epitopes (which are generally also activation epitopes) and shows decreased expression of ligand-attenuated binding site (LABS) epitopes (such as mAb 13 for the ␤ 1 subunit, see Ref. 11). The conformational states are in equilibrium; therefore, antibodies that recognize activation epitopes or LIBS tend to cause activation and stabilize the ligand-occupied state. Conversely, antibodies that recognize LABS appear to block ligand binding by preventing conformati...