FOR THE SCANDINAVIAN SIMVASTATIN SURVIVAL STUDY GROUPOBJECTIVE -To assess the effect of simvastatin treatment on the risk of cardiovascular events in nondiabetic patients with coronary heart disease (CHD) with and without the metabolic syndrome, as defined by the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP-III).RESEARCH DESIGN AND METHODS -Subgroup analyses were performed on data from 3,933 nondiabetic patients with clinically established CHD, serum total cholesterol level 5.5-8.0 mmol/l, and serum triglyceride level Յ2.5 mmol/l who were participating in the Scandinavian Simvastatin Survival Study (4S), a randomized, placebo-controlled trial. End points were total mortality, coronary mortality, major CHD event, myocardial revascularization, any CHD event, stroke, and any atherosclerotic event.RESULTS -Over the 5.4-year median follow-up period, simvastatin produced similar changes in serum lipid levels in 893 patients with the metabolic syndrome and in 3,040 patients without the metabolic syndrome. The relative risks of main end points in simvastatin-treated patients compared with placebo-treated patients with the metabolic syndrome were as follows: total mortality 0.54 (95% CI 0.36 -0.82), coronary mortality 0.39 (0.23-0.65), major CHD event 0.59 (0.45-0.77), and any atherosclerotic event 0.69 (0.56 -0.84). The corresponding RRs in patients without the metabolic syndrome were 0.72 (0.56 -0.91), 0.62 (0.45-0.84), 0.71 (0.61-0.82), and 0.76 (0.68 -0.85).CONCLUSIONS -Nondiabetic CHD patients with or without the metabolic syndrome realize from simvastatin treatment a similar, substantial relative reduction in the risk of cardiovascular events. The absolute benefit may be greater in patients with the metabolic syndrome because they are at a higher absolute risk.

Defects in the apoptotic machinery can contribute to tumor formation and resistance to treatment, creating a need to identify new agents that kill cancer cells by alternative mechanisms. To this end, we examined the cytotoxic properties of a novel peptide, CT20p, derived from the C-terminal, alpha-9 helix of Bax, an amphipathic domain with putative membrane binding properties. Like many anti-microbial peptides, CT20p contains clusters of hydrophobic and cationic residues that could enable the peptide to associate with lipid membranes. CT20p caused the release of calcein from mitochondrial-like lipid vesicles without disrupting vesicle integrity and, when expressed as a fusion protein in cells, localized to mitochondria. The amphipathic nature of CT20p allowed it to be encapsulated in polymeric nanoparticles (NPs) that have the capacity to harbor targeting molecules, dyes or drugs. The resulting CT20p-NPs proved an effective killer of colon and breast cancer cells in vitro and in vivo, using a murine breast cancer tumor model. By introducing CT20p to Bax deficient cells, we demonstrated that the peptide’s lethal activity was independent of endogenous Bax. CT20p also caused an increase in the mitochondrial membrane potential that was followed by plasma membrane rupture and cell death, without the characteristic membrane asymmetry associated with apoptosis. We determined that cell death triggered by the CT20p-NPs was minimally dependent on effector caspases and resistant Bcl-2 over-expression, suggesting that it was independent of the intrinsic apoptotic death pathway. Furthermore, use of CT20p with the apoptosis-inducing drug, cisplatin, resulted in additive toxicity. These results reveal the novel features of CT20p that allow nanoparticle-mediated delivery to tumors and the potential application in combination therapies to activate multiple death pathways in cancer cells.

This study explores the roles of Bax and other Bcl-2 family members play in arsenic trioxide (As 2 O 3 )-induced apoptosis. We showed that As 2 O 3 treatment triggered Bax conformational change and subsequent translocation from cytosol to mitochondria to form various multimeric homo-oligomers in IM-9 cells. On the other hand, human leukemic Jurkat cells deficient in Bax showed dramatically reduced apoptosis in response to As 2 O 3 . Stable overexpression of Bcl-2 in IM-9 cells (IM-9/Bcl-2) inhibited As 2 O 3 -mediated Bax activation and apoptosis, and this inhibition could be partially averted by cellpermeable Bid-Bcl-2 homology (BH)3 peptide. Meanwhile, Bax conformational change and oligomerization induced by As 2 O 3 were not inhibited by the pancaspase inhibitor z-VAD-fmk, although Bid cleavage could be completely abolished. Bax activation by As 2 O 3 seemed to require stress-induced intracellular reactive oxygen species (ROS), since the ROS scavengers (N-acetyl-Lcysteine and lipoic acid) could completely block the conformational change and translocation of Bax from cytosol to mitochondria. These data suggest that As 2 O 3 might exert the cell killing in part by inducing Bax activation through a Bcl-2-suppressible pathway in hematopoietic cells that is caspase independent and intracellular ROS regulated.

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Abstract:We present experimental results on post-tuning the dispersion of a two-dimensional photonic crystal waveguide made from Ge 33 As 12 Se 55 chalcogenide glass by exploiting the material photosensitivity to nearbandgap light. The change in the refractive index and volume of the material in response to exposure to 633nm light resulted in a shift of more than 5nm in the resonant coupling wavelength between a tapered optical fiber and the modes of a W1 waveguide. This represents a first proof of principle demonstration of the photosensitive post-tuning of a planar photonic crystal device.

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We demonstrate the spectral and spatial reconfigurability of photonic crystal double-heterostructure cavities in silicon by microfluidic infiltration of selected air holes. The lengths of the microfluidic cavities are changed by adjusting the region of infiltrated holes in steps of several microns. We systematically investigate the spectral signature of these cavities, showing high Q-factor resonances for a broad range of cavity lengths. The fluid can be removed by immersing the device in toluene, offering complete reconfigurability. Our cavity writing technique allows for tolerances in the infiltration process and provides flexibility as it can be employed at any time after photonic crystal fabrication.

We demonstrate postprocessed and reconfigurable photonic crystal double-heterostructure cavities via selective fluid infiltration. We experimentally investigate the microfluidic cavities via evanescent probing from a tapered fiber at telecommunication wavelengths. Fabry-Pérot fringes associated with modes of the induced cavity are in good agreement with the theory. We also demonstrate a cavity with quality factor Q=4300. Our defect-writing technique does not require nanometer-scale alterations in lattice geometry and may be undertaken at any time after photonic crystal waveguide fabrication.