Deficiencies with current aortic endografts.

Endovascular aortic aneurysm repair (EVAR) has currently replaced open surgical repair as the primary method for treating aneurysm disease of the abdominal aorta and common iliac artery. Current EVAR devices, despite undergoing multiple improvement iterations, continue to have relatively high secondary intervention rates. Device migration, endoleak and limb occlusion continue to be challenges not completely met by any of the current devices. Investigational devices presently in clinical trials may provide significant resolution for many of the identified endograft deficiencies.

Heparin inhibition of autonomous growth implicates amphiregulin as an autocrine growth factor for normal human mammary epithelial cells.

Normal human mammary epithelial cells (HMECs) proliferate in a serum-free defined growth medium in the absence of epidermal growth factor (Li and Shipley, 1991). Amphiregulin (AR) is a heparin-regulated, EGF-like growth factor. Our observation that one strain of HMECs produce AR mRNA (Cook et al., 1991 a) stimulated us to determine whether AR expression was a common phenomenon in HMECs and whether AR could act as an autocrine growth factor to support the EGF-independent growth of these cells. In this study, we detected high levels of AR expression in four separate HMEC strains while one immortal mammary cell line (HBL-100) and six mammary tumor-derived cell lines had low to undetectable levels of AR. The EGF-independent growth of HMECs was blocked by the addition of heparin or a monoclonal anti-EGF receptor antibody to the culture medium, implicating AR as an autocrine growth mediator. This hypothesis is further supported by the fact that medium conditioned by HMECs contains secreted AR protein. A mammary tumor-derived cell line, Hs578T, which proliferates in an EGF-independent manner, does not express detectable levels of AR and is not growth inhibited by heparin. Examination of the same cell types for expression of transforming growth factor type-alpha (TGF-alpha) mRNA revealed coordinate expression of AR and TGF-alpha in these cells. These data suggest that both AR and TGF-alpha mRNA are produced in much greater abundance by normal HMECs than in tumor-derived cells in culture, and that AR is an important autostimulatory factor for the growth of normal HMECs.

The epithelin precursor encodes two proteins with opposing activities on epithelial cell growth.

Epithelin 1 and 2 were originally purified from rat kidneys based on their ability to inhibit the growth of A-431 human epidermoid carcinoma cells (Shoyab, M., McDonald, V.L., Byles, C., Todaro, G.J., and Plowman, G.D. (1990) Proc. Natl. Acad. Sci. U.S.A. 87, 7912-7916). This study presents the complete amino acid sequence of these two growth factors and the cloning of their cDNA from rat, mouse, and human sources. Epithelins 1 and 2 are 56- and 57-amino acid polypeptides, respectively, and share 47% amino acid sequence identity with the conserved spacing of 12 cysteine residues. Molecular cloning revealed that both proteins are encoded by a single precursor that contains 7 1/2 copies of this novel 12-cysteine motif, 2 of which represent the known active molecules. Recombinant expression in COS cells demonstrated that the epithelin 1 protein was mitogenic on rodent keratinocytes and fibroblasts. In contrast, epithelin 2 had no activity on these cells, but at high concentrations was capable of antagonizing the growth proliferative activities of epithelin 1. Northern analysis shows the epithelin mRNA to be expressed in many types of epithelial cells. The broad expression profile of epithelin transcripts, along with the opposing activities of the two mature protein products, implicates these factors as natural mediators of epithelial homeostasis.

Regulation of amphiregulin mRNA by TGF-beta in the human lung adenocarcinoma cell line A549.

Transforming growth factor beta is a strong growth inhibitor for many types of normal and transformed cells, although little is known on the mechanism of this anti-proliferative effect. The human lung adenocarcinoma cell line A549 is growth arrested by TGF-beta 1 and serves as a model for studying this effect. We describe that, concurrent with the inhibition of A549 cell growth, TGF-beta 1 treatment causes a dramatic reduction in the level of expression of the amphiregulin (AR) gene, a recently identified member of the EGF/TGF alpha family. Similar results were also observed with TGF-beta 2. Peak inhibition occurred at 24 hr of treatment and was reversible upon removal of TGF-beta 1. The level of AR protein secreted by A549 cells was also decreased by TGF-beta 1. In contrast, TGF-alpha mRNA was not detected in these cells regardless of TGF-beta 1 treatment. Another TGF-beta inhibited cell line, PC-3 (human prostatic adenocarcinoma) also exhibited a decrease in AR message levels following exposure to TGF-beta 1. The growth inhibitory effects of TGF-beta may in part be mediated by modulation of AR expression.

Modulation of hnRNP A1 protein gene expression by epidermal growth factor in Rat-1 cells.

The levels of mRNA encoding hnRNP core protein A1 have been compared in quiescent and proliferating Rat-1 embryonic fibroblasts. Northern blot hybridization analyses using probes made from an A1 cDNA clone, lambda HDP-182, isolated by Cobianchi et al. (J. Biol. Chem. 261:3536-2543 (1986] indicated that three sizes of poly A + RNAs, 1.6, 2.0, & 4.0 kb, have extensive sequence homology. The levels of all three A1 RNA species are responsive to the proliferation state of the cells. Stimulation of quiescent Rat-1 cells with serum or epidermal growth factor resulted in a 2- to 5-fold increase in the levels of each of these three RNAs that was evident after 2 hours and reached a peak after about 8 hours. Addition of the protein synthesis inhibitor, cycloheximide, along with epidermal growth factor completely blocked the upsurge in A1 RNA levels. Thus, the A1 RNA species are not primary transcriptional targets of epidermal growth factor but do show an induction pattern similar to mRNAs encoding some glycolytic enzymes.