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Psychological distress, which can begin with cancer diagnosis and continue with treatment, is linked with circadian and endocrine disruption. In turn, circadian/endocrine factors are potent modulators of cancer progression. We hypothesized that circadian rest-activity rhythm disruption, distress, and diurnal cortisol rhythms would be associated with biomarkers of tumor progression in the peripheral blood of women awaiting breast cancer surgery. Breast cancer patients (n=43) provided actigraphic data on rest-activity rhythm, cancer-specific distress (IES, POMS), saliva samples for assessment of diurnal cortisol rhythm, cortisol awakening response (CAR), and diurnal mean. Ten potential markers of tumor progression were quantified in serum samples and grouped by exploratory factor analysis. Analyses yielded three factors, which appear to include biomarkers reflecting different aspects of tumor progression. Elevated factor scores indicate both high levels and strong clustering among serum signals. Factor 1 included VEGF, MMP-9, and TGF-β; suggesting tumor invasion/immunosuppression. Factor 2 included IL-1β, TNF-α, IL-6R, MCP-1; suggesting inflammation/chemotaxis. Factor 3 included IL-6, IL-12, IFN-γ; suggesting inflammation/TH1-type immunity. Hierarchical regressions adjusting age, stage and socioeconomic status examined associations of circadian, distress, and endocrine variables with these three factor scores. Patients with poor circadian coordination as measured by rest-activity rhythms had higher Factor 1 scores (R(2)=.160, p=.038). Patients with elevated CAR also had higher Factor 1 scores (R(2)=.293, p=.020). These relationships appeared to be driven largely by VEGF concentrations. Distress was not related to tumor-relevant biomarkers, and no other significant relationships emerged. Women with strong circadian activity rhythms showed less evidence of tumor promotion and/or progression as indicated by peripheral blood biomarkers. The study was not equipped to discern the cause of these associations. Circadian/endocrine aberrations may be a manifestation of systemic effects of aggressive tumors. Alternatively, these results raise the possibility that, among patients with active breast tumors, disruption of circadian activity rhythms and elevated CAR may facilitate tumor promotion and progression., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Chronic inflammation and oxidative stress have been implicated in the pathophysiology of Major Depressive Disorder (MDD), as well as in a number of chronic medical conditions. The aim of this study was to examine the relationship between peripheral inflammatory and oxidative stress markers in un-medicated subjects with MDD compared to non-depressed healthy controls and compared to subjects with MDD after antidepressant treatment. We examined the relationships between IL-6, IL-10, and the IL-6/IL-10 inflammatory ratio vs. F2-isoprostanes (F2-IsoP), a marker of oxidative stress, in un-medicated MDD patients (n=20) before and after 8 weeks of open-label sertraline treatment (n=17), compared to healthy non-depressed controls (n=20). Among the un-medicated MDD subjects, F2-IsoP concentrations were positively correlated with IL-6 concentrations (p<0.05) and were negatively correlated with IL-10 concentrations (p<0.01). Accordingly, F2-IsoP concentrations were positively correlated with the ratio of IL-6/IL-10 (p<0.01). In contrast, in the control group, there were no significant correlations between F2-IsoPs and either cytokine or their ratio. After MDD subjects were treated with sertraline for 8 weeks, F2-IsoPs were no longer significantly correlated with IL-6, IL-10 or the IL-6/IL-10 ratio. These data suggest oxidative stress and inflammatory processes are positively associated in untreated MDD. Our findings are consistent with the hypothesis that the homeostatic buffering mechanisms regulating oxidation and inflammation in healthy individuals become dysregulated in untreated MDD, and may be improved with antidepressant treatment. These findings may help explain the increased risk of comorbid medical illnesses in MDD., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Unlabelled: Cognitive and affective responses to acute stress influence pro-inflammatory cytokine reactivity, and peripheral cytokines (particularly interleukin-1 beta (IL-1β)), can act on the brain to promote depressive symptoms. It is unknown whether acute stress-induced changes in positive affect and cognitions (POS) and pro-inflammatory reactivity predict future depressive symptoms. We examined acute stress responses among women, to determine prospective predictors of depressive symptoms., Hypotheses: (1) Stress-induced decreases in POS will be associated with stress-related increases in circulating IL-1β. (2) Acute stress-induced decreases in POS and increases in IL-1β reactivity will predict increases in depressive symptoms 1 year later. Thirty-five post-menopausal women were exposed to acute stress with the Trier Social Stress Task (TSST) and provided blood samples under resting conditions and 30 min after the conclusion of the TSST, which were assayed for IL-1β. IL-1β reactivity was quantified as post minus pre-TSST. Failure to maintain POS was quantified as the decrease in POS during the TSST. Change in depressive symptoms from the study baseline to the following year was determined. Greater acute stress-induced declines in POS were significantly associated with increased IL-1β reactivity (p≤.02), which significantly predicted increases in depressive symptoms over the following year (p<.01), controlling for age, body mass index, chronic stress, antidepressant use and baseline depressive symptoms. IL-1β reactivity was a significant mediator of the relationship between POS decline and future increases in depressive symptoms (p=.04). Difficulty maintaining positivity under stress and heightened pro-inflammatory reactivity may be markers and/or mechanisms of risk for future increases in depressive symptoms., (Copyright © 2011 Elsevier Inc. All rights reserved.)

The combination of less positive and more negative expectations for the future (i.e., lower optimism and higher pessimism) increases risk for disease and early mortality. We tested the possibility that expectancies might influence health outcomes by altering the rate of biological aging, specifically of the immune system (immunosenescence). However, no studies to date have examined associations between optimism or pessimism and indicators of immunosenescence such as leukocyte telomere length (TL) and interleukin-6 (IL-6) levels. We investigated whether dispositional tendencies towards optimism and pessimism were associated with TL and IL-6 in a sample of 36 healthy post-menopausal women. Multiple regression analyses where optimism and pessimism were entered simultaneously, and chronological age and caregiver status were controlled, indicated that pessimism was independently associated with shorter TL (beta=-.68, p=.001) and higher IL-6 concentrations (beta=.50, p=.02). In contrast, optimism was not independently associated with either measure of immunosenescence. These findings suggest that dispositional pessimism may increase IL-6 and accelerate rate of telomere shortening. Mechanistic causal relationships between these parameters need to be investigated.

Delayed type hypersensitivity (DTH) reactions are antigen-specific, cell-mediated immune responses which, depending on the antigen involved, mediate beneficial (resistance to viruses, bacteria, fungi, and certain tumors) or harmful (allergic dermatitis, autoimmunity) aspects of immune function. We have shown that acute stress administered immediately before antigenic challenge results in a significant enhancement of a skin DTH response in rats. A stress-induced trafficking or redeployment of leukocytes to the skin may be one of the factors mediating this immunoenhancement. Here we investigate the effects of varying the duration, intensity, and chronicity of stress on the DTH response and on changes in blood leukocyte distribution and glucocorticoid levels. Acute stress administered for 2 h prior to antigenic challenge, significantly enhanced the DTH response. Increasing the duration of stress from 2 h to 5 h produced the same magnitude enhancement in cutaneous DTH. Moreover, increasing the intensity of acute stress produced a significantly larger enhancement of the DTH response which was accompanied by increasing magnitudes of leukocyte redeployment. In contrast, chronic stress suppressed the DTH response when it was administered for 3 weeks before sensitization and either discontinued upon sensitization, or continued an additional week until challenge, or extended for one week after challenge. The stress-induced redeployment of peripheral blood lymphocytes was attenuated with increasing exposure to chronic stress and correlated with attenuated glucocorticoid responsivity. These results suggest that stress-induced alterations in lymphocyte redeployment may play an important role in mediating the bi-directional effects of acute versus chronic stress on cell-mediated immunity in vivo.

In this study, we examined hormonal regulation of the distribution profiles of leukocyte subpopulations in the peripheral blood of rats. Flow cytometric analysis revealed significant and selective changes in the numbers and the percentages of peripheral blood leukocyte subpopulations which were a function of diurnal variations in hormone secretion and hormonal changes induced by acute stress. Changes in numbers and percentages of leukocyte subpopulations, which varied with time of day, were similar to changes observed under stress conditions. At the beginning of the rat's active period, and after 1 h of restraint stress, there was a significant reduction in numbers of leukocytes and lymphocytes. This reduction was primarily accounted for by a decrease in numbers of B cells, natural killer cells, monocytes (diurnal study), and helper T cells (diurnal study). There was also a significant decrease in the percentage of lymphocytes which was mirrored by an increase in the percentage of neutrophils in the peripheral blood. Peripheral blood leukocyte numbers were inversely related to plasma corticosterone levels. These results suggest that the endocrine system plays a role in the regulation of immune cell turnover and/or redistribution between immune compartments under conditions of normal daily experiences, namely, the diurnal cycle, and mild acute stress. They also suggest that these effects are selective for certain subpopulations of leukocytes.