In vitro inhibition of human sarcoma cells' invasive ability by bis(5-amidino-2-benzimidazolyl)methane--a novel esteroprotease inhibitor.

Bis(5-amidino-2-benzimidazolyl)methane (BABIM) is a synthetic aromatic amidine compound which has a number of important biochemical effects, including inhibition of a family of esteroproteases (trypsin, urokinase, plasmin) previously linked to the complex process of tumor invasion. Previous work has suggested that exogenous natural protease inhibitors can block invasion of tumor cells across basement membranes (BM) in vitro. The authors studied the effect of BABIM on the human cell line HT-1080 with the use of a quantitative in vitro amnion invasion assay system. They have verified the ability of these cells to grow in nude mice and metastasize via the lymphatics or blood vessels on the basis of the route of administration of the inoculum. Cells which were able to actively cross the entire BM were trapped on filters and counted by both brightfield microscopy and by beta scintillation counting of cells whose DNA was labeled with tritiated thymidine. In agreement with either counting technique, BABIM, at a concentration of 10(-4) M, significantly inhibited invasion (P less than 0.005) over the 7-day course of the experiments. Under these conditions, the inhibitor was nontoxic and did not alter the attachment of the cells to the amniotic membrane. Furthermore, a highly significant inhibition of invasion (P less than 0.001) was also demonstrated across a variation in molar concentration of BABIM of more than 2 orders of magnitude. Most remarkably, cells were initially inhibited in their ability to invade in the presence of between 10(-9) and 10(-3) M BABIM. Measurement of Type IV specific collagenase in media from these cells shows a significant inhibition of activity in the presence of BABIM. These results suggest two, not necessarily exclusive, alternative interpretations: first, that inhibition of the proteolytic steps along the pathway of activation of basement membrane degrading enzymes results in inhibition of invasion; second, that arginine directed esteroproteases may work in concert with cellular collagenolytic metalloproteinases in the process of invasion by human tumor cells through native matrix barriers

A Spectroscopic Study of the H-alpha Surface Brightness Profiles in the Outer Disks of Galaxies

The surface brightness profile of H-alpha emission in galaxies is generally thought to be confined by a sharp truncation, sometimes speculated to coincide with a star formation threshold. Over the past years, observational evidence for both old and young stellar populations, as well as individual H II regions, has demonstrated that the outer disk is an actively evolving part of a galaxy. To provide constraints on the origin of the aforementioned H-alpha truncation and the relation of H-alpha emission in the outer disk to the underlying stellar population, we measure the shape of the outer H-alpha surface brightness profile of 15 isolated, edge-on late-type disk galaxies using deep, long-slit spectroscopy. Tracing H-alpha emission up to 50% beyond the optical radius, R_25, we find a composite H-alpha surface brightness profile, well described by a broken-exponential law, that drops more steeply in the outer disk, but which is not truncated. The stellar continuum and H-alpha surface brightness both exhibit a break at ~0.7 R_25, but the H-alpha emission drops more steeply than the stellar continuum beyond that break. Although profiles with truncations or single exponential laws correctly describe the H-alpha surface brightness profiles of some individual galaxies, flexible broken-exponentials are required in most cases and are therefore the more appropriate generic description. The common existence of a significant second surface brightness component beyond the H-alpha break radius disfavors the hypothesis that this break is a purely stochastic effect.Comment: 13 pages, 8 figures, accepted for publication in MNRA

BRCA2 polymorphic stop codon K3326X and the risk of breast, prostate, and ovarian cancers

Background: The K3326X variant in BRCA2 (BRCA2*c.9976A>T; p.Lys3326*; rs11571833) has been found to be associated with small increased risks of breast cancer. However, it is not clear to what extent linkage disequilibrium with fully pathogenic mutations might account for this association. There is scant information about the effect of K3326X in other hormone-related cancers. Methods: Using weighted logistic regression, we analyzed data from the large iCOGS study including 76 637 cancer case patients and 83 796 control patients to estimate odds ratios (ORw) and 95% confidence intervals (CIs) for K3326X variant carriers in relation to breast, ovarian, and prostate cancer risks, with weights defined as probability of not having a pathogenic BRCA2 variant. Using Cox proportional hazards modeling, we also examined the associations of K3326X with breast and ovarian cancer risks among 7183 BRCA1 variant carriers. All statistical tests were two-sided. Results: The K3326X variant was associated with breast (ORw = 1.28, 95% CI = 1.17 to 1.40, P = 5.9x10- 6) and invasive ovarian cancer (ORw = 1.26, 95% CI = 1.10 to 1.43, P = 3.8x10-3). These associations were stronger for serous ovarian cancer and for estrogen receptor–negative breast cancer (ORw = 1.46, 95% CI = 1.2 to 1.70, P = 3.4x10-5 and ORw = 1.50, 95% CI = 1.28 to 1.76, P = 4.1x10-5, respectively). For BRCA1 mutation carriers, there was a statistically significant inverse association of the K3326X variant with risk of ovarian cancer (HR = 0.43, 95% CI = 0.22 to 0.84, P = .013) but no association with breast cancer. No association with prostate cancer was observed. Conclusions: Our study provides evidence that the K3326X variant is associated with risk of developing breast and ovarian cancers independent of other pathogenic variants in BRCA2. Further studies are needed to determine the biological mechanism of action responsible for these associations