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

项目总结/摘要 这项研究的主要目的是确定和比较唾液分泌的昼夜节律模式， 促肿瘤和炎性细胞因子的浓度，特别是白细胞介素-6（IL-6）和白细胞介素-4（IL-4）。 1 β（IL-1β），在妇科肿瘤患者中，年龄和种族/民族与健康对照相匹配。健康 对照被具体地概念化为没有癌症史的个体（即，非癌症 对照组）。这项研究的目的是进一步研究心理和生理之间的关系， 应力（即，主观[感知压力]和客观[唾液皮质醇]压力测量）和昼夜唾液 细胞因子的表达。越来越多的经验证据为可能的亲- 炎症和免疫反应、心理应激和昼夜节律失调的致瘤作用 生物钟基因表达可能最终影响癌症的发生、进展和复发。 进一步确定了炎症、免疫过程、昼夜节律之间可能的多方向联系， 节奏和心理压力，其中（1）外周时钟振荡的同步被认为是 调节通过各种相互作用的过程，涉及交感神经系统（SNS），下丘脑- 垂体肾上腺（HPA）轴，和激素的周期性释放（例如，糖皮质激素），（2）激素分泌， 免疫细胞过程（例如，细胞因子的循环浓度、白细胞迁移、T细胞生成），以及 炎症反应又受到中枢和外周神经系统维持的昼夜模式的调节， （3）心理应激可通过HPA轴和自主神经触发下游反应 如果是慢性的，可能会使免疫系统功能失调， 微环境，并增加肿瘤人群发病的总体风险。3 -11可用性和 唾液生物标志物的可获得性为其他方法无法获得的广泛分析打开了大门。15，16 具体地，唾液样本可以在允许评估的时间内每天多次收集 炎症过程的昼夜变化，可以帮助辨别昼夜节律之间的联系， 失调，免疫功能改变，心理障碍和肿瘤生长， 扩散，以更好地为美国目前约1500万癌症患者提供服务。 陈述1 - 2，13，17拟议研究的工作假设是：（1）促肿瘤发生的唾液浓度 非癌症对照的细胞因子将在醒来时达到峰值，并在一天中稳步下降， IL-6除外，其在晚上将有次高峰，（2）妇科肿瘤患者将 与非癌症对照组相比，所有唾液标志物的昼夜节律均显著变钝，以及（3）主要 癌症状态对昼夜唾液细胞因子斜率的影响将受到感知压力和皮质醇的调节 斜坡

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.