The impact of in utero BPA exposure on the development of breast cancer

Previous studies have shown that in utero exposure to diethylstilbestrol (DES), a synthetic form of estrogen, increases the risk of developing various forms of cancer, including breast cancer, later in life. Bisphenol A (BPA) has been shown to act as a synthetic estrogen, and acts similarly to DES in rodents. Both compounds belong to a class of compounds known as endocrine disrupting compounds (EDCs), known to have hormonal activity. In utero BPA exposure can also increase the risk of developing breast cancer in rodents. The exact mechanism by which BPA alters the morphology of the mammary gland to create this susceptibility, however, is unknown. Using immunohistochemistry, we have shown that BPA affects the expression of two key proteins, Ki67 and ERα, in the stroma, correlating to significant defects in the epithelium. These data suggest that BPA induced alterations in the stroma may affect the epithelial phenotype, specifically ductal branching. One cell type of the stroma, fibroblasts, contribute to the production of the extracellular matrix (ECM), which provides structural support for the epithelial ducts. These cells also communicate with the developing epithelium through secreted proteins. Therefore, fibroblasts are critical to both the structure and function of the mammary gland. Alterations to fibroblasts have the potential to lead to changes that can disrupt normal development and cellular function in the mammary gland. We performed transcriptome analysis and identified the extracellular matrix to be significantly altered in the BPA exposed mammary glands, so collagendeposition was investigated. We demonstrate that BPA exposed fibroblasts have increased collagen in the mammary glands, a molecular phenotype shown to increase cancer risk.Mayers Summer Research ScholarshipNo embargoAcademic Major: Biolog

Preliminary Investigation of Continuous Self-Improvement & Problem-Focused Coping Styles

https://fuse.franklin.edu/ss2018/1036/thumbnail.jp

Macrophage-Specific Chemokines Induced via Innate Immunity by Amino Acid Copolymers and Their Role in EAE

The random amino acid copolymer poly(Y,E,A,K)n (Copaxone®) is widely used in multiple sclerosis treatment and a second generation copolymer poly(Y,F,A,K)n with enhanced efficacy in experimental autoimmune encephalomyelitis in mice has been described. A major mechanism through which copolymers function to ameliorate disease is the generation of immunosuppressive IL-10-secreting regulatory T cells entering the CNS. In addition, the antigen presenting cell to which these copolymers bind through MHC Class II proteins may have an important role. Here, both CCL22 (a Th2 cell chemoattractant) in large amounts and CXCL13 in much smaller amounts are shown to be secreted after administration of YFAK to mice and to a smaller extent by YEAK parallel to their serum concentrations. Moreover, bone marrow-derived macrophages secrete CCL22 in vitro in response to YFAK and to higher concentrations of YEAK. Strikingly, these chemokines are also secreted into serum of MHC Class II −/− mice, indicating that an innate immune receptor on these cells also has an important role. Thus, both the innate and the adaptive immune systems are involved in the mechanism of EAE amelioration by YFAK. The enhanced ability of YFAK to stimulate the innate immune system may account for its enhanced efficacy in EAE treatment

Nitric oxide and pulmonary hypertension

Pulmonary hypertension is a serious complication of a number of lung and heart diseases that is characterized by peripheral vascular structural remodeling and loss of vascular tone. Nitric oxide can modulate vascular injury and interrupt elevation of pulmonary vascular resistance selectively; however, it can also produce cytotoxic oxygen radicals and exert cytotoxic and antiplatelet effects. The balance between the protective and adverse effects of nitric oxide is determined by the relative amount of nitric oxide and reactive radicals. Nitric oxide has been shown to be clinically effective in the treatment of congenital heart disease, mitrial valvular disease combined with pulmonary hypertension and in orthotropic cardiac transplantation patients. Additionally, new therapeutic modalities for the treatment of pulmonary hypertension, phosphodiesterase inhibitors, natriuretic peptides and aqueous nitric oxide are also effective for treatment of elevated pulmonary vascular resistance

Patterns of Fever in Children After Primary Treatment for Kawasaki Disease

OBJECTIVE: To determine if fever in the early post intravenous immunoglobulin (IVIG) time period (first 36 hours after IVIG completion) for Kawasaki disease (KD), with or without additional infliximab, can predict IVIG resistance and coronary artery abnormalities (CAA). METHODS: Acute KD subjects enrolled in a clinical trial of infliximab plus IVIG (n=96) versus placebo/IVIG (n=94) had temperatures recorded every 6 hours after completion of IVIG infusion. Fever was defined as temperature ≥38.0°C; patients with persistent or recrudescent fever ≥36 hours after completion of IVIG were classified as IVIG-resistant. Multivariable logistic regression by fever pattern was performed to predict outcomes (IVIG resistance and CAA). RESULTS: There was no difference in the time to defervescence between the infliximab/IVIG group (n=96) versus placebo/IVIG group (n= 94). There was no fever after completion of IVIG in the majority of subjects [66% of those with no CAA (n=139) and 76.5% of those with CAA, (n=51)]. Although subjects with at least one fever 24–36 hours post-IVIG had a higher probability of IVIG resistance (OR=30.6 [95%CI 6.7–139.8] p<0.0001), fever at 24–36 hours was not associated with higher likelihood of CAA. There were also 11% (n=19) of IVIG responders who had fever at 24–36 hours post-IVIG. The majority of subjects with CAA (43 of 51, 84.3%) were identified by the initial echocardiogram, so the effect of fever on development of CAA could not be assessed. CONCLUSION: Fever in the first 36 hours following IVIG completion is not predictive of CAA. Our data support refraining from re-treatment until 36 hours after completion of IVIG

Characterization of binding, functional activity, and contractile responses of the selective 5-HT1F receptor agonist lasmiditan

Background and Purpose: Triptans are 5-HT1B/1D receptor agonists (that also display 5-HT1F receptor affinity) with antimigraine action, contraindicated in patients with coronary artery disease due to their vasoconstrictor properties. Conversely, lasmiditan was developed as an antimigraine 5-HT1F receptor agonist. To assess the selectivity and cardiovascular effects of lasmiditan, we investigated the binding, functional activity, and in vitro/in vivo vascular effects of lasmiditan and compared it to sumatriptan. Experimental Approach: Binding and second messenger activity assays of lasmiditan and other serotoninergic agonists were performed for human 5-HT1A, 5-HT1B, 5-HT1D, 5-ht1E, 5-HT1F, 5-HT2A, 5-HT2B, and 5-HT7 receptors, and the results were correlated with their potency to constrict isolated human coronary arteries (HCAs). Furthermore, concentration–response curves to lasmiditan and sumatriptan were performed in proximal and distal HCA, internal mammary, and middle meningeal arteries. Finally, anaesthetized female beagle dogs received i.v. infusions of lasmiditan or sumatriptan in escalating cumulative doses, and carotid and coronary artery diameters were measured. Key Results: Lasmiditan showed high selectivity for 5-HT1F receptors. Moreover, the functional potency of the analysed compounds to inhibit cAMP increase through 5-HT1B receptor activation positively correlated with their potency to contract HCA. In isolated human arteries, sumatriptan, but not lasmiditan, induced contractions. Likewise, in vivo, sumatriptan decreased coronary and carotid artery diameters at clinically relevant doses, while lasmiditan was devoid of vasoconstrictor activity at all doses tested. Conclusions and Implications: Lasmiditan is a selective 5-HT1F receptor agonist devoid of vasoconstrictor activity. This may represent a cardiovascular safety advantage when compared to the triptans

TCT-174 Comparison of Thrombotic Risk Between Coronary Artery Aneurysm and Coronary Ectasia Based on Hemodynamic Parameters

Background The aneurysmal form of the coronary arteries is mainly classified into 2 Categories: coronary artery aneurysm (CAA) and coronary artery ectasia (CAE). The corresponding thrombotic risk of these vascular phenotypes is assessed by the maximum luminal diameter and z-scores in the clinical routines. However, their morphology and local hemodynamic status can be much different. In this study, we compared the thrombotic risk of fusiform CAA with CAE on the basis of hemodynamic indexes, while having the same diameters and z-scores. Methods Idealized axisymmetric 3-dimensional models of CAA and CAE were designed with the same maximum diameter and z-scores. Computational fluid dynamics were used to simulate the blood flow in these 2 cases. The hemodynamic indexes time-averaged wall shear stress (TAWSS) and relative residence time (RRT) were calculated for each case. Generally, regions with low TAWSS and high RRT are correlated with an elevated risk for atherosclerosis and thrombosis. Results The streamlines at peak flow in these 2 cases are illustrated in Figure 1. The results indicate that although the mean TAWSS (0.999 [Pa] vs 1.065 [Pa]) and the mean RRT (2.84 [1/Pa] vs 2.58 [1/Pa]) for CAA and CAE are in the same range. However, it is observed that the area exposed to vortices and circulatory flow in CAE is much larger than in CAA, which are candidate sites for thrombus formation

Effect of Beta Blockers on the Hemodynamics and Thrombotic Risk of Coronary Artery Aneurysms in Kawasaki Disease

This study aims to simulate beta blockers’ (BB) effects on coronary artery aneurysms’ (CAA) hemodynamics and thrombotic risk in Kawasaki disease (KD). BB are recommended in cases of large aneurysms due to their anti-ischemic effect. Coronary blood flow (CBF) was simulated in KD patient-specific CAA models using computational fluid dynamics. Hemodynamic indices that correlate with thrombotic risk were calculated following two possible responses to BB: (1) preserved coronary flow (third BB generation) and (2) reduction in coronary flow (first and second BB generations) at reduced heart rate. Following CBF reduction scenario, mean TAWSS and HOLMES significantly decreased compared to normal conditions, leading to a potential increase in thrombotic risk. Preserved CBF at lower heart rates, mimicking the response to vasodilating BBs, does not significantly affect local CAA hemodynamics compared with baseline, while achieving the desired anti-ischemic effects. Different BB generations lead to different hemodynamic responses in CAA. Graphical abstract: [Figure not available: see fulltext.