Diurnal Variations in Salivary Concentrations of Pro-Tumorigenic Cytokines and Possible Effects of Psycho-Physiological Stress in Gynecologic Cancer Patients and Matched Healthy Controls

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PROJECT SUMMARY/ABSTRACT The primary goal of the proposed study is to identify and compare the diurnal circadian pattern of salivary concentrations of pro-tumorigenic and inflammatory cytokines, specifically interleukin-6 (IL-6) and interleukin- 1beta (IL-1β), in gynecologic oncology patients and age and race/ethnicity matched healthy controls. Healthy controls are specifically conceptualized as individuals who do not have a history of cancer (i.e., non-cancer control group). The proposed study further aims to examine the relationships between psycho-physiological stress (i.e., subjective [perceived stress] and objective [salivary cortisol] measures of stress) and diurnal salivary cytokine expression in these two groups. Mounting empirical evidence provides support for possible pro- tumorigenic effects of inflammatory and immune responses, psychological stress, and dysregulation of circadian clock gene expression that may ultimately impact cancer initiation, progression, and recurrence.3-7 Researchers have further identified possible multi-directional associations among inflammation, immune processes, circadian rhythms, and psychological stress wherein (1) synchronization of peripheral clock oscillations are thought to be regulated through various interacting processes involving the sympathetic nervous system (SNS), hypothalamic- pituitary adrenal (HPA) axis, and cyclical release of hormone (e.g., glucocorticoids), (2) hormone secretion, immune cell processes (e.g., circulating concentration of cytokines, Leukocyte migration, T cell genesis), and inflammatory responses are, in turn, regulated by diurnal patterns maintained by the central and peripheral clocks, and (3) psychological stress can trigger a downstream reaction via the HPA axis and autonomic nervous system (ANS) that, if chronic, can dysregulate immune system functioning, negatively impact tumor microenvironment, and increase overall risk of morbidity in oncology populations.3-11 The availability and accessibility of salivary biomarkers opens the door to a breadth of analyses otherwise inaccessible.15,16 Specifically, salivary samples can be collected multiple times per day across time allowing for the assessment of diurnal variations in inflammatory processes that can help discern associations among circadian dysregulations, alterations in immune functioning, psychological disturbances, and tumor growth and proliferation in an effort to better serve the estimated 15 million people currently living with cancer in the United States.1-2,13,17 Working hypotheses for the proposed study are: (1) salivary concentrations of pro-tumorigenic cytokines of non-cancer controls will peak upon awakening and steadily decrease throughout the day, with the exception of IL-6 for which there will be a secondary peak in the evening, (2) gynecologic oncology patients will have significantly blunted diurnal rhythms for all salivary markers compared to non-cancer controls, and (3) main effects of cancer status on diurnal salivary cytokine slopes will be moderated by perceived stress and cortisol slopes.