Advanced glycation end products are elevated in estrogen receptor-positive breast cancer patients, alter response to therapy, and can be targeted by lifestyle intervention.

PURPOSE: Lifestyle factors associated with personal behavior can alter tumor-associated biological pathways and thereby increase cancer risk, growth, and disease recurrence. Advanced glycation end products (AGEs) are reactive metabolites produced endogenously as a by-product of normal metabolism. A Western lifestyle also promotes AGE accumulation in the body which is associated with disease phenotypes through modification of the genome, protein crosslinking/dysfunction, and aberrant cell signaling. Given the links between lifestyle, AGEs, and disease, we examined the association between dietary-AGEs and breast cancer. METHODS: We evaluated AGE levels in bio-specimens from estrogen receptor-positive (ER+) and estrogen receptor-negative (ER-) breast cancer patients, examined their role in therapy resistance, and assessed the ability of lifestyle intervention to reduce circulating AGE levels in ER+ breast cancer survivors. RESULTS: An association between ER status and AGE levels was observed in tumor and serum samples. AGE treatment of ER+ breast cancer cells altered ERα phosphorylation and promoted resistance to tamoxifen therapy. In a proof of concept study, physical activity and dietary intervention was shown to be viable options for reducing circulating AGE levels in breast cancer survivors. CONCLUSIONS: There is a potential prognostic and therapeutic role for lifestyle derived AGEs in breast cancer. Given the potential benefits of lifestyle intervention on incidence and mortality, opportunities exist for the development of community health and nutritional programs aimed at reducing AGE exposure in order to improve breast cancer prevention and treatment outcomes.

The Impact of Physician Race and Sex on Patient Ranking of Physician Competence and Perception of Leadership Ability.

Background Biases affect patient perceptions of their physician and influence the physician-patient relationship. While racial disparities in care and inequities in the healthcare workforce are well-documented, the impact of physician race on patient perceptions remains unclear. We aimed to investigate the association of physician race and sex on patient perceptions during simulated preoperative encounters. Methods Three hundred patients recruited consecutively in the Preanesthesia Evaluation and Testing Center viewed pictures of 4 anesthesiologists (black male, white male, black female, white female) in random order while listening to a set of paired audio recordings describing general anesthesia. Participants ranked each anesthesiologist on confidence, intelligence, and likelihood of choosing the anesthesiologist to care for their family member, and chose the one anesthesiologist most like a leader. Results Compared to white anesthesiologists, black anesthesiologists had greater odds of being ranked more confident (OR, 1.45; 95% CI, 1.10 to 1.89; P=0.008) and being considered a leader (OR, 2.06; 95% CI, 1.50 to 2.84; P<0.0001). Among white participants, black anesthesiologists had greater odds of being ranked more intelligent (OR, 2.08; 95% CI, 1.54 to 2.81; P<0.0001) and were more likely to be chosen to care for a family member (OR, 2.26; 95% CI, 1.66 to 3.08; P<0.0001). Female anesthesiologists had greater odds of being ranked more intelligent (OR, 1.36; 95% CI, 1.08 to 1.71; P=0.009) and were more likely to be chosen to care for a family member (OR, 1.58; 95% CI, 1.27 to 1.97; P<0.001) compared with male anesthesiologists. Conclusions Contrary to our hypothesis, patients ranked black physicians more highly on multiple competence and leadership quality metrics. Our data likely highlight the role social desirability bias may play in studies of racial disparities within medicine.

The Flaw of Medicine: Addressing Racial and Gender Disparities in Critical Care.

The age of modern medicine has ushered in remarkable advances and with them increased longevity of life. The questions are, however: Has everyone benefited from these developments equally? and Do all lives truly matter? The presence of gender and racial health disparities indicates that there is work still left to be done. The first target of intervention may well be the medical establishment itself. The literature presented in this article identifies potential targets for interventions and future areas of exploration.

Two Sides of the Same Coin: Addressing Racial and Gender Disparities Among Physicians and the Impact on the Community They Serve.

The influence of historical cultural norms is evident when analyzing the physician demographics in the United States. To this day, there exists a paucity in diversity as it pertains to gender balance and ethnicity. This phenomenon is particularly concerning when studies support the notion that race and gender concordance are associated with improved outcomes. The literature presented in this article identifies potential targets for interventions on how to attract, train, and retain minority physicians.

Endothelin-A receptor inhibition after cardiopulmonary bypass: cytokines and receptor activation.

BACKGROUND: Basic studies have suggested that cross-talk exists between the endothelin-A receptor (ET-AR) and tumor necrosis factor signaling pathway. This study tested the hypothesis that administration of an ET-AR antagonist at the separation from cardiopulmonary bypass would alter the tumor necrosis factor activation in the early postoperative period. METHODS: Patients (n = 44) were randomly allocated to receive bolus infusion of vehicle, 0.1, 0.5, 1, or 2 mg/kg of the ET-AR antagonist (sitaxsentan), at the separation from cardiopulmonary bypass (n = 9, 9, 9, 9, and 8, respectively). Plasma levels of tumor necrosis factor-alpha and soluble tumor necrosis factor receptor 1 and 2 were measured. RESULTS: Compared with the vehicle group at 24 hours, plasma levels of tumor necrosis factor-alpha and tumor necrosis factor receptor 2 (indicative of receptor activation) were reduced in the 1 mg/kg ET-AR antagonist group (by approximately 13 pg/mL and approximately 0.5 ng/mL, respectively; p < 0.05). Plasma tumor necrosis factor receptor I levels also decreased (by approximately 1 ng/mL) after infusion of the higher doses of the ET-AR antagonist and remained lower (by approximately 3 ng/mL) at 24 hours after infusion (p < 0.05). In addition, a dose effect was observed between the ET-AR antagonist and these indices of tumor necrosis factor activation (p < 0.01). CONCLUSIONS: This study demonstrated a mechanistic relationship between the ET-AR and tumor necrosis factor receptor activation in the post-cardiac surgery period. Thus, in addition to the potential cardiovascular effects, a selective ET-AR antagonist can modify other biological processes relevant to the post-cardiac surgery setting.

Selective endothelin-A receptor inhibition after cardiac surgery: a safety and feasibility study.

BACKGROUND: Increased synthesis and release of the bioactive peptide endothelin has been shown to change hemodynamics and postoperative recovery after cardiac surgery. However, the clinical effects of selective interruption of endothelin signaling have not been studied. Because the endothelin-A (ET-A) receptor subtype is the primary cardiovascular effector for endothelin, this study used the ET-A receptor antagonist sitaxsentan sodium (TBC11251Na) to evaluate: (1) dose-dependent changes in pulmonary artery pressure (PAP) and pulmonary (PVRI) and systemic (SVRI) vascular resistance index in patients undergoing on-pump coronary revascularization; and (2) whether ET-RA administration was associated with increased adverse events. METHODS: Patients (n = 44, age, 62 +/- 1 years) were randomized to receive vehicle (n = 9) or different bolus infusions of ET-A receptor antagonist: 0.1 (n = 9), 0.5 (n = 9) 1.0 (n = 9), and 2.0 mg/kg (n = 8) at separation from cardiopulmonary bypass (CPB). Adverse events were tabulated until hospital discharge. Results were expressed as changes from a composite baseline value, or from time 0 due to a high degree of intrapatient measurement variability in the postoperative period. RESULTS: PAP increased by 27% +/- 13% from baseline (19 +/- 1 mm Hg) in the vehicle group at 6 hours post-CPB (p < 0.05). PAP fell from this post-CPB vehicle value in a dose-dependent manner with the ET-A receptor antagonist; with a significant reduction observed at 2 mg/kg (7% +/- 8% increase from baseline, p < 0.05). PVRI was reduced by 28.6% +/- 16% from baseline (249 +/- 22 dyn x s x cm(-5) x m(-2)) in the 2 mg/kg ET-A receptor antagonist group at 30 minutes post-CPB and remained reduced up to 6 hours post-CPB (p < 0.05). SVRI was reduced from baseline (2770 +/- 106 dyn x s x cm(-5) x m(-2)) by 51% +/- 6% in the 2.0 mg/kg ET-A receptor antagonist group at 30 minutes post-CPB (p < 0.05) and remained reduced up to 6 hours post-CPB. A total of 203 adverse events were tabulated in the postoperative period and were equally distributed across the five treatment groups, with no direct attributions to ET-A receptor antagonist treatment. CONCLUSIONS: This unique study demonstrates that heightened endothelin-A receptor activation contributes to hemodynamic changes in patients after CPB. Selective inhibition of the endothelin receptor system can be successfully and safely performed in patients undergoing cardiac surgery and thereby reveals a potential, and clinically relevant therapeutic target.