Tumor endothelium is critical for solid tumor growth and is a potential site for anticancer drug action. Within 2 h, etoposide caused marked DNA strand breakage in xenograft tumor-derived endothelial ...cells (TDECs). Etoposide-induced DNA breakage was inhibited by culturing TDECs on gelatin, type IV collagen, laminin, fibronectin, and the integrin ligand hexapeptide, GRGDSP, but not the inactive peptide, GRADSP. It was also inhibited when TDECs were on surfaces coated with antibodies to alpha 5, beta 1, or beta 3 integrin subunits and by clustering integrins with soluble antibodies. After 8 h with etoposide, TDECs detached from the monolayer, and 50-kb DNA fragments were seen. Fibronectin inhibited both processes. Thus, integrins are survival factors for TDEC that inhibit the genotoxicity of etoposide and may influence the sensitivity of tumors to drugs.
The determinants of {±1}-matrices are calculated via the oriented hypergraphic Laplacian and summing over incidence generalizations of vertex cycle-covers. These cycle-covers are signed and ...partitioned into families based on their hyperedge containment. Every non-edge-monic family is shown to contribute a net value of 0 to the Laplacian, while each edge-monic family is shown to sum to the absolute value of the determinant of the original incidence matrix. Simple symmetries are identified as well as their relationship to Hadamard's maximum determinant problem. Finally, the entries of the incidence matrix are reclaimed using only the signs of an adjacency-minimal set of cycle-covers from an edge-monic family.
In the early 1930s, a formalin-inactivated toxoid against botulinum neurotoxin was first tested in humans. In 1965, a pentavalent botulinum toxoid (PBT) received Investigational New Drug (IND) status ...under the Centers for Disease Control's IND 161 (for at-risk workers), and in 1991 under the United States Army's Office of the Surgeon General IND 3723 (for military deployment). This PBT vaccine has been shown to be safe, with over 20,000 injections given to date, and continues to be used in at-risk individuals. During the past decade, recombinant DNA technology has been employed to develop second-generation vaccines to prevent botulism. Recombinant subunit vaccines utilizing the receptor-binding domains of botulinum neurotoxin (BoNT) have been shown to be safe and efficacious in protecting animal models against BoNT serotypes A, B, C1, D, E, and F. In 2004, the first recombinant subunit vaccine rBV A/B (Pichia pastoris) vaccine was tested in humans during a phase I clinical trial. Results from that study demonstrated that the recombinant bivalent vaccine was safe and well tolerated at all dosage levels tested and stimulated serotype-specific neutralizing antibodies among the majority of vaccine recipients.
Tyrosine phosphatases (PTPases) dephosphorylate phosphotyrosines while dual-specificity phosphatases (DSPases) dephosphorylate contiguous and semicontiguous phosphothreonine and phosphotyrosine on ...cyclin dependent kinases and mitogen-activated protein kinases. Consequently, PTPases and DSPases have a central role controlling signal transduction and cell cycle progression. Currently, there are few readily available potent inhibitors of PTPases or DSPases other than vanadate. Using a pharmacophore modeled on natural product inhibitors of phosphothreonine phosphatases, we generated a refined library of novel, phosphate-free, small-molecule compounds synthesized by a parallel, solid-phase combinatorial-based approach. Among the initial 18 members of this targeted diversity library, we identified several inhibitors of DSPases: Cdc25A, -B, and -C and the PTPase PTP1B. These compounds at 100 μM did not significantly inhibit the protein serine/threonine phosphatases PP1 and PP2A. Kinetic studies with two members of this library indicated competitive inhibition for Cdc25 DSPases and noncompetitive inhibition for PTP1B. Compound AC-αα69 had a K i of approximately 10 μM for recombinant human Cdc25A, -B, and -C, and a K i of 0.85 μM for the PTP1B. The marked differences in Cdc25 inhibition as compared to PTP1B inhibition seen with relatively modest chemical modifications in the modular side chains demonstrate the structurally demanding nature of the DSPase catalytic site distinct from the PTPase catalytic site. These results represent the first fundamental advance toward a readily modifiable pharmacophore for synthetic PTPase and DSPase inhibitors and illustrate the significant potential of a combinatorial-based strategy that supplements the rational design of a core structure by a randomized variation of peripheral substituents.
A compelling feature of relativistic mean-field phenomenology has been the reproduction of spin-orbit splittings in finite nuclei after fitting only to equilibrium properties of infinite nuclear ...matter. This successful result occurs when the velocity dependence of the equivalent central potential that leads to saturation arises primarily because of a reduced nucleon effective mass. The spin-orbit interaction is then also specified when one works in a four-component Dirac framework. Here the nature of the spin-orbit force in more general chiral effective field theories of nuclei is examined, with an emphasis on the role of the tensor coupling of the isoscalar vector meson (ω) to the nucleon.
Results of a clinical study using intravenous (IV) ribavirin for treating Department of Defense personnel with hemorrhagic fever with renal syndrome (HFRS) acquired in Korea from 1987 to 2005 were ...reviewed to determine the clinical course of HFRS treated with IV ribavirin. A total of 38 individuals enrolled in the study had subsequent serological confirmation of HFRS. Four of the 38 individuals received three or fewer doses of ribavirin and were excluded from treatment analysis. Of the remaining 34 individuals, oliguria was present in one individual at treatment initiation; none of the remaining 33 subjects developed oliguria or required dialysis. The mean peak serum creatinine was 3.46
mg/dl and occurred on day 2 of ribavirin therapy. Both the peak serum creatinine and the onset of polyuria occurred on mean day 6.8 of illness. Reversible hemolytic anemia was the main adverse event of ribavirin, with a ≥25% decrease in hematocrit observed in 26/34 (76.5%) individuals. While inability to adjust for all baseline variables prevents comparison to historical cohorts in Korea where oliguria has been reported in 39–69% cases and dialysis required in approximately 40% HFRS cases caused by Hantaan virus, the occurrence of 3% oliguria and 0% dialysis requirement in the treatment cohort is supportive of a previous placebo-controlled HFRS trial in China where IV ribavirin given early resulted in decreased occurrence of oliguria and decreased severity of renal insufficiency.
Over the past several years, funding for biodefense research has increased dramatically, leading to the possibility of increased laboratoryacquired infections with potential bioterrorism agents. The ...Special Immunizations Program at United States Army Medical Research Institute of Infectious Diseases reviewed its policy and management of potential occupational exposures (1989-2002) to assess guidelines for determining the risk of exposure and disease and to determine criteria for initiating postexposure prophylaxis (PEP). Initiating antibiotic PEP was based primarily on exposure risk but was also influenced by vaccination status and agent virulence. PEP was given to nearly all moderate- and high-risk bacterial exposures, regardless of vaccination status, to most unvaccinated and subsets of vaccinated minimal-risk exposures, but generally not to negligible-risk exposures. Algorithms for evaluating and managing potential exposures are presented to provide guidance to other agencies as they begin to work with these agents.
There is increasing evidence supporting the role of platelets in atherosclerotic vascular disease. The G-protein-coupled receptor P2Y12 is a central mediator of platelet activation and aggregation ...but has also been linked to platelet-independent vascular disease. Ticagrelor is an oral P2Y12 antagonist that is used as a standard treatment in patients after acute myocardial infarction. However, the effects of ticagrelor on advanced atherosclerosis have not been investigated.
Twenty-week-old apolipoprotein-E-deficient mice received standard chow or standard chow supplemented with 0.15% ticagrelor (approximately 270 mg/kg/day) for 25 weeks. The lesion area was evaluated in the aortic sinus by Movat's pentachrome staining and lesion composition, thickness of the fibrous cap, and size of the necrotic core evaluated by morphometry. RAW 264.7 macrophages were serum starved and treated with ticagrelor in vitro for the detection and quantification of apoptosis. In addition, oxLDL uptake in RAW 264.7 macrophages was evaluated.
A trend toward the reduction of total lesion size was detected. However, data did not reach the levels of significance (control, n=11, 565,881 μm(2) interquartile range {IQR} 454,778-603,925 μm(2) versus ticagrelor, n=13, 462,595 μm(2) IQR 379,740-546,037 μm(2); P=0.1). A significant reduction in the relative area of the necrotic core (control, n=11, 0.46 IQR 0.4-0.51 versus ticagrelor, n=13, 0.34 IQR 0.31-0.39; P=0.008), and a significant increase in fibrous caps thickness (control, n=11, 3.7 μm IQR 3.4-4.2 μm versus ticagrelor, n=13, 4.7 IQR 4.3-5.5 μm, P=0.04) were seen in ticagrelor-treated mice. In vitro studies demonstrated a reduction in apoptotic RAW 264.7 macrophages (control 0.07±0.03 versus ticagrelor 0.03±0.03; P=0.0002) when incubated with ticagrelor. Uptake of oxLDL in RAW 264.7 was significantly reduced when treated with ticagrelor (control 9.2 IQR 5.3-12.9 versus ticagrelor 6.4 IQR 2.5-9.5, P=0.02).
The present study demonstrates for the first time a plaque-stabilizing effect of ticagrelor in a model of advanced vascular disease, potentially induced by a reduction of oxLDL uptake or an inhibition of apoptosis as seen in vitro.
PDF
