Divergent Immune Responses in Behaviorally-Inhibited vs. Non-Inhibited Male Rats

Stable behavioral traits (temperament, personality) often predict health outcomes. Temperament-specific differences in immune function could explain temperament-specific health outcomes, however, we have limited information on whether immune function varies by personality. In the present study, we examined the relationship between a basic behavioral trait (behavioral-inhibition vs. non-inhibition) and two immune responses (innate inflammation and delayed-type hypersensitivity, DTH) in a rodent model. In humans, behavioral inhibition (fearful temperament) is associated with altered stress physiology and allergies. In laboratory rats, the trait is associated with elevated glucocorticoid production. We hypothesized that behavioral inhibition is associated with glucocorticoid resistance and dampened T-helper 1 cell responses often associated with chronic stress and allergies. Further, this immune profile would predict poorly-regulated innate inflammation and dampened DTH. In male Sprague-Dawley rats, we quantified consistent behavioral phenotypes by measuring latency to contact two kinds of novelty (object vs. social), then measured lipopolysaccharide(LPS)-induced innate inflammation or keyhole limpet hemocyanin(KLH)-induced DTH. Behaviorally-inhibited rats had heightened glucocorticoid and interleukin-6 responses to a low/moderate dose of LPS and reduced DTH swelling to KLH re-exposure compared to non-inhibited rats. These results suggest that behavioral inhibition is associated with a glucocorticoid resistant state with poorly regulated innate inflammation and dampened cell-mediated immune responses. This immune profile may be associated with exaggerated T-helper 2 responses, which could set the stage for an allergic/asthmatic/atopic predisposition in inhibited individuals. Human and animal models of temperament-specific immune responses represent an area for further exploration of mechanisms involved in individual differences in health

A phase II study of combined ridaforolimus and dalotuzumab compared with exemestane in patients with estrogen receptor-positive breast cancer

Purpose: Combining the mTOR inhibitor ridaforolimus and the anti-IGFR antibody dalotuzumab demonstrated antitumor activity, including partial responses, in estrogen receptor (ER)-positive advanced breast cancer, especially in high proliferation tumors (Ki67 > 15%). Methods: This randomized, multicenter, international, phase II study enrolled postmenopausal women with advanced ER-positive breast cancer previously treated with a nonsteroidal aromatase inhibitor (NCT01234857). Patients were randomized to either oral ridaforolimus 30 mg daily for 5 of 7 days (once daily [qd] × 5 days/week) plus intravenous dalotuzumab 10 mg/kg/week or oral exemestane 25 mg/day, and stratified by Ki67 status. Due to a high incidence of stomatitis in the ridaforolimus–dalotuzumab group, two sequential, nonrandomized, reduced-dose cohorts were explored with ridaforolimus 20 and 10 mg qd × 5 days/week. The primary endpoint was progression-free survival (PFS). Results: Median PFS was 21.4 weeks for ridaforolimus 30 mg qd × 5 days/week plus dalotuzumab 10 mg/kg (n = 29) and 24.3 weeks for exemestane (n = 33; hazard ratio = 1.00; P = 0.5). Overall survival and objective response rates were similar between treatment arms. The incidence of drug-related, nonserious, and serious adverse events was higher with ridaforolimus/dalotuzumab (any ridaforolimus dose) than with exemestane. Lowering the ridaforolimus dose reduced the incidence of grade 3 stomatitis, but overall toxicity remained higher than acceptable at all doses without improved efficacy. Conclusions: The combination of ridaforolimus plus dalotuzumab was no more effective than exemestane in patients with advanced ER-positive breast cancer, and the incidence of adverse events was higher. Therefore, the combination is not being further pursued.SCOPUS: ar.jinfo:eu-repo/semantics/publishe