uPA and PAI-1 in breast cancer: review of their clinical utility and current validation in the prospective NNBC-3 trial.

The plasminogen activator system is a complex system with multiple interactions and members participating in fibrinolysis, cell migration, angiogenesis, wound healing, embryogenesis, tumor cell dissemination, and metastasis in a variety of solid tumors. Increased levels of uPA and/or PAI-1 in primary tumor tissues of breast cancer patients correlate with tumor aggressiveness and poor clinical outcome. Patients with high tumor tissue antigen content of uPA and/or PAI-1 have a worse probability of disease-free and overall survival than patients with low levels of both of the biomarkers, serving as prognostic markers. The clinical utility of uPA and PAI-1 has been proven on the highest level of evidence (LOE-I). Next to being clinically useful prognostic factors allowing estimates of the course of disease in early breast cancer, uPA and PAI-1 may also serve as predictive factors predicting response to systemic therapy. Node-negative primary breast cancer patients with high uPA/PAI-1 levels benefit significantly from adjuvant chemotherapy. The aim of the ongoing NNBC-3 trial is to determine the benefits of a sequential anthracycline-docetaxel regimen in high-risk node-negative breast cancer patients compared to the current standard of anthracycline-based chemotherapy. At present, uPA and PAI-1 provide the unique opportunity to allow validated and clinically relevant risk assessment of breast cancer patients, over and above that provided by established risk factors. Therefore, in the evidence-based, annually updated AGO guidelines for breast cancer management, the German Working Group for Gynecological Oncology (AGO) has recommended both biomarkers as risk-group-classification markers for routine clinical decision making in node-negative breast cancer, next to established clinical and histomorphological factors.

Oxygen uptake and local Po2 profiles in submerged larvae of phaeoxantha klugii (Coleoptera: Cicindelidae), as well as their metabolic rate in air.

We studied whether oxygen uptake from the surrounding water might enhance survival in submerged third instar larvae of Phaeoxantha klugii, a tiger beetle from the central Amazonian floodplains. Local oxygen partial pressures (Po(2)) were measured with microcoaxial needle electrodes close to larvae submerged in initially air-saturated still water. The Po(2) profiles showed that the larvae exploit oxygen from the aquatic medium. Metabolism in the air of more or less resting larvae was determined by measuring the rate of CO(2) production (sV dot co2) with an infrared gas analyzer at 29 degrees C. The sV dot co2 was around 1.8 mu L g(-1) min(-1), equivalent to an oxygen consumption rate (sV dot o2) of 1.8-2.6 mu L g(-1) min(-1). Oxygen consumption (V dot o2) of individually submerged larvae measured in closed respiration chambers at 19-10.3 kPa Po(2) (initially air saturated, 29 degrees C) ranged between 0.05 and 0.2 mu L min(-1) and was not correlated with body mass. The sV dot o2 ranged between 0.1 and 0.4 mu L min(-1), that is, 4%-22% of the metabolic rate measured in air. Mean V dot o2 decreased with declining Po(2); however, some individuals showed contrary patterns. V dot o2 was additionally measured in dormant larvae, in larvae submerged for 1-2 d in open water or for 30-49 d within sediment, as well as in larvae exposed to anoxia before the measurements. The range of V dot o2 was similar in all groups, indicating that the larvae exploit oxygen from the water whenever available. Similar V dot o2 across the whole range of body mass investigated (0.31-0.76 g) suggests that oxygen uptake occurs by spiracular uptake. Assuming that larvae survive for some time at rates comparable to depressed metabolic rates reported for other insect species, it can be concluded that oxygen uptake from water can sustain aerobic metabolism even under quite severe hypoxia. It might therefore play an important role for survival during inundation periods.