Thioredoxin reductase mediates cell death effects of the combination of beta interferon and retinoic acid.

Interferons (IFNs) and retinoids are potent biological response modifiers. By using JAK-STAT pathways, IFNs regulate the expression of genes involved in antiviral, antitumor, and immunomodulatory actions. Retinoids exert their cell growth-regulatory effects via nuclear receptors, which also function as transcription factors. Although these ligands act through distinct mechanisms, several studies have shown that the combination of IFNs and retinoids synergistically inhibits cell growth. We have previously reported that IFN-beta-all-trans-retinoic acid (RA) combination is a more potent growth suppressor of human tumor xenografts in vivo than either agent alone. Furthermore, the IFN-RA combination causes cell death in several tumor cell lines in vitro. However, the molecular basis for these growth-suppressive actions is unknown. It has been suggested that certain gene products, which mediate the antiviral actions of IFNs, are also responsible for the antitumor actions of the IFN-RA combination. However, we did not find a correlation between their activities and cell death. Therefore, we have used an antisense knockout approach to directly identify the gene products that mediate cell death and have isolated several genes associated with retinoid-IFN-induced mortality (GRIM). In this investigation, we characterized one of the GRIM cDNAs, GRIM-12. Sequence analysis suggests that the GRIM-12 product is identical to human thioredoxin reductase (TR). TR is posttranscriptionally induced by the IFN-RA combination in human breast carcinoma cells. Overexpression of GRIM-12 causes a small amount of cell death and further enhances the susceptibility of cells to IFN-RA-induced death. Dominant negative inhibitors directed against TR inhibit its cell death-inducing functions. Interference with TR enzymatic activity led to growth promotion in the presence of the IFN-RA combination. Thus, these studies identify a novel function for TR in cell growth regulation.

Initial experience with a new balloon-on-a-wire catheter: the Bijou.

This paper presents our initial experience with a new low-profile balloon "on-a-wire" catheter, the Bijou. The concept of this balloon is to provide an additional side lumen with the advantages of (1) the ability to measure pressure gradient, (2) the possibility of drug infusion, and (3) the ability to advance a steerable guidewire through this side lumen. The balloon has been tested in 15 patients; 14 underwent an elective procedure for stable angina pectoris (with 2 cases of restenosis) and one an emergency angioplasty in a case of acute myocardial infarction. The stenosis was located on the left anterior descending artery in 11 procedures, on the right in 3, on a marginal branch in 2, on the circumflex and a saphenous vein graft in 1. All stenoses could be dilated successfully (residual stenosis < 25%). The transstenotic pressure gradient felt from 49 +/- 13 mmHg to 7 +/- 4 mm Hg after angioplasty. Except for an uncomplicated dissection in 3 patients, no other complication was noted. With this new catheter, the double-lumen configuration adds the advantages of an "over-the-wire" to an "on-a-wire" system.