Cytoadherence of red blood cells (RBCs) invaded by Plasmodium falciparum parasites is an important contributor to the sequestration of RBCs causing reduced microcirculatory flow associated with fatal malaria syndromes. The phenomenon involves a parasite–derived variant antigen, the P. falciparum erythrocyte membrane protein 1 (PfEMP1), and several human host receptors, such as chondroitin sulfate A (CSA) which has been explicitly implicated in placental malaria. Elucidating the molecular mechanisms of cytoadherence requires quantitative evaluation, under physiologically relevant conditions, of the specific receptor–ligand interactions associated with pathological states of cell–cell adhesion. Such quantitative studies have not been reported thus far for P. falciparum malaria under conditions of febrile temperatures that accompany malarial infections. In this study, single RBCs infected with P. falciparum parasites (CSA binding phenotype), in trophozoite stage, have been engaged in mechanical contact with the surface of surrogate cells specifically expressing CSA, so as to quantify cytoadherence to human syncytiotrophoblasts in a controlled manner. From these measurements, a mean rupture force of 43 pN was estimated for the CSA–PfEMP1 complex at 37 °C. Experiments carried out at febrile temperature showed a noticeable decrease in CSA–PfEMP1 rupture force (by about 23% at 41 °C and about 20% after a 40 °C heat–treatment), in association with an increased binding frequency. The decrease in rupture force points to a weakened receptor–ligand complex after exposure to febrile temperature, while the rise in binding frequency suggests an additional display of nonspecific binding molecules on the RBC surface. The present work establishes a robust experimental method for the quantitative assessment of cytoadherence of diseased cells with specific molecule–mediated binding.
555 Background: Accumulating data suggest that body weight and physical activity may affect breast cancer risk and outcomes. Biological mechanisms underlying these relationships are not clear. Studies have demonstrated that high levels of insulin, often seen in obese and sedentary individuals, are also associated with an increased risk of breast cancer recurrence and breast cancer-related death. We sought to analyze whether exercise lowers insulin levels in a population of breast cancer survivors. Methods: Inactive women with early stage breast cancer who had completed adjuvant treatment were randomized to a 16 week, mixed cardiovascular and strength training exercise intervention, or to a normal care control group. Target exercise goals included 2 supervised strength training sessions and 90 minutes of unsupervised cardiovascular exercise each week. Fasting insulin and glucose levels, as well as measurement of weight, body composition, and circumference at the waist and hip, were collected at baseline and after 16 weeks in both groups, and changes in these measures were assessed. Results: One hundred and one women were randomized. Comparison of changes in anthropometric measures are presented in Table 1 . Baseline insulin levels were similar in the 2 groups. After the 16-week exercise or control period, insulin levels decreased by 2.86 μIU/ml in the exercise group (p=0.03), and by 0.27 μIU/ml in the control group (p=0.65). A comparison of the change in insulin levels across time in the 2 groups approached statistical significance (p=0.07). There was also a trend toward improvements in insulin sensitivity in the exercise group (p=0.09), with no change seen in fasting glucose levels. Conclusions: Physical activity was associated with a decrease in insulin levels and in hip circumference in breast cancer survivors. The relationship between physical activity and breast cancer prognosis may be mediated, at least partially, through changes in insulin levels and/or changes in fat mass or deposition. [Table: see text] No significant financial relationships to disclose.
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