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Early life stress (ELS) is common in the United States and worldwide, and contributes to the development of psychopathology in individuals with these experiences and their offspring. A growing body of research suggests that early life stress may contribute to adverse health partly through modulation of immune (and particularly inflammatory) responses. Therefore, increased maternal prenatal inflammation has been proposed as a mechanistic pathway by which the observed cross-generational effects of parental early life stress on child neuropsychiatric outcomes may be exerted. We examined associations between early life stress and molecular markers of inflammation (specifically pro-inflammatory gene expression and receptor-mediated transcription factor activity) and a commonly studied circulating marker of inflammation (C-Reactive Protein) in a diverse group of women in or near their third trimester of pregnancy, covarying for age, race/ethnicity, BMI, concurrent infection, concurrent perceived stress, and per capita household income. Mothers who experienced higher levels of early life stress had significantly increased pro-inflammatory (NF-κB) and decreased anti-viral (IRF) transcription factor activity. Transcripts that were up or down regulated in mothers with high ELS were preferentially derived from both CD16+ and CD16- monocytes. Early life stress was not associated with elevated CRP. Taken together, these findings provide preliminary evidence for an association between ELS and a pro-inflammatory transcriptional phenotype during pregnancy that may serve as a mechanistic pathway for cross-generational transmission of the effects of early life stress on mental and physical health.

BackgroundThe Pathways to Wellness trial tested the efficacy of 2 interventions for younger breast cancer survivors: mindful awareness practices (MAPs) and survivorship education (SE). This planned secondary analysis examines intervention effects on stress, positive psychological outcomes, and inflammation (Clincaltrials.gov NCT03025139).MethodsWomen diagnosed with breast cancer at or before age 50 years who had completed treatment and had elevated depressive symptoms were randomly assigned to 6 weeks of MAPs, SE, or wait-list control (WLC). Assessments conducted at pre- and postintervention and at 3- and 6-month follow-up measured general stress perceptions, cancer-related intrusive thoughts and worry, positive affect, meaning and peace in life, altruism and empathy, and markers of inflammation. Analyses compared change in outcomes over time in each intervention group relative to WLC using linear mixed models.ResultsA total 247 women were randomly assigned to MAPs (n = 85), SE (n = 81), or WLC (n = 81). MAPs statistically significantly decreased intrusive thoughts and worry at postintervention and 3-month follow-up relative to WLC (P

Stress can lead to depression, in part because of activation of inflammatory mechanisms. It is therefore critical to identify resilience factors that can buffer against these effects, but no research to date has evaluated whether psychosocial resilience mitigates the effects of stress on inflammation-associated depressive symptoms. We therefore examined psychosocial resources known to buffer against stress in a longitudinal study of women with breast cancer (N = 187). Depressive symptoms and inflammation were measured over a 2-year period extending from after diagnosis into survivorship. Cancer-related stress and psychosocial resources-social support, optimism, positive affect, mastery, self-esteem, and mindfulness-were measured after diagnosis. As hypothesized, women who reported having more psychosocial resources showed weaker associations between stress and depressive symptoms and weaker associations between stress and inflammation-related depressive symptoms. Results highlight the importance of psychosocial resilience by demonstrating a relationship between psychosocial resources and sensitivity to inflammation-associated depressive symptoms.

BackgroundInflammation contributes to poor behavioral, functional, and clinical outcomes in cancer survivors. We examined whether standard cancer treatments-radiation and chemotherapy-led to acute and persistent changes in circulating markers of inflammation in breast cancer patients.MethodsA total of 192 women diagnosed with early stage breast cancer provided blood samples before and after completion of radiation and/or chemotherapy and at 6-, 12-, and 18-month posttreatment follow-ups. Samples were assayed for circulating inflammatory markers, including tumor necrosis factor-α (TNF-α) and interleukin (IL)-6, downstream markers of their activity (soluble TNF receptor type II [sTNF-RII], C reactive protein), and other inflammatory mediators (IL-8, interferon-γ [IFN-γ]). Analyses evaluated within-group changes in inflammatory markers in 4 treatment groups: no radiation or chemotherapy (n = 39), radiation only (n = 77), chemotherapy only (n = 18), and chemotherapy with radiation (n = 58).ResultsPatients treated with chemotherapy showed statistically significant increases in circulating concentrations of TNF-α, sTNF-RII, IL-6, and IFN-γ from pre- to posttreatment, with parameter estimates in standard deviation units ranging from 0.55 to 1.20. Those who received chemotherapy with radiation also showed statistically significant increases in IL-8 over this period. Statistically significant increases in TNF-α, sTNF-RII, IL-6, IFN-γ, and IL-8 persisted at 6, 12, and 18 months posttreatment among patients treated with chemotherapy and radiation (all P < .05). Patients treated with radiation only showed a statistically significant increase in IL-8 at 18 months posttreatment; no increases in any markers were observed in patients treated with surgery only.ConclusionsChemotherapy is associated with acute increases in systemic inflammation that persist for months after treatment completion in patients who also receive radiation therapy. These increases may contribute to common behavioral symptoms and other comorbidities in cancer survivors.

Parasympathetic nervous system activity can downregulate inflammation, but it remains unclear how parasympathetic nervous system activity relates to antiviral activity. The present study examined associations between parasympathetic nervous system activity and cellular antiviral gene regulation in 90 adolescents (Mage = 16.28, SD = 0.73; 51.1% female) who provided blood samples and measures of cardiac respiratory sinus arrhythmia (RSA), twice, five weeks apart. Using a multilevel analytic framework, we found that higher RSA (an indicator of higher parasympathetic nervous system activity)-both at rest and during paced breathing-was associated with higher expression of Type I interferon (IFN) response genes in circulating leukocytes, even after adjusting for demographic and biological covariates. RSA was not associated with a parallel measure of inflammatory gene expression. These results identify a previously unrecognized immunoregulatory aspect of autonomic nervous system function and highlight a potential biological pathway by which parasympathetic nervous system activity may relate to health.

BackgroundStress precipitates depression and may do so in part by increasing susceptibility to inflammation-induced depressive symptoms. However, this has not been examined among individuals facing a major life stressor. Accordingly, the present study tested the moderating role of stress on the longitudinal association between inflammation and depressive symptoms among women with breast cancer.MethodsWomen recently diagnosed with early-stage breast cancer (N = 187) were enrolled before starting adjuvant/neoadjuvant treatment. Blood draws and self-reported depressive symptoms were collected pre-treatment, post-treatment, and at 6, 12, and 18-month post-treatment follow ups. C-reactive protein (CRP) was used to index inflammation. Measures of psychological stress, including cancer-related stress, general stress perceptions, and childhood stress, were administered pre-treatment.ResultsStress moderated the association between CRP and depressive symptoms, such that higher levels of CRP were associated with elevated depressive symptoms only among women who reported high cancer-related stress (β = 0.080, p = .002) and perceived stress (β = 0.053, p = .044); childhood stress effects were non-significant. Moreover, elevated CRP was associated with increased odds of exhibiting clinically significant depressive symptoms (OR = 1.64, p

BackgroundFatigue is a common and expected side effect of cancer treatment. However, the majority of studies to date have focused on average levels of fatigue, which may obscure important individual differences in the severity and course of fatigue over time. The current study was designed to identify distinct trajectories of fatigue from diagnosis into survivorship in a longitudinal study of women with early-stage breast cancer.MethodsWomen with stage 0 to stage IIIA breast cancer (270 women) were recruited before (neo)adjuvant therapy with radiotherapy, chemotherapy, and/or endocrine therapy and completed assessments at baseline; posttreatment; and at 6 months, 12 months, and 18 months of follow-up. Growth mixture modeling was used to identify trajectories of fatigue, and differences among the trajectory groups with regard to demographic, medical, and psychosocial variables were examined.ResultsFive distinct trajectories of fatigue were identified: Stable Low (66%), with low levels of fatigue across assessments; Stable High (13%), with high fatigue across assessments; Decreasing (4%), with high fatigue at baseline that resolved over time; Increasing (9%), with low fatigue at baseline that increased over time; and Reactive (8%), with increased fatigue after treatment that resolved over time. Both psychological and treatment-related factors were found to be associated with fatigue trajectories, with psychological factors most strongly linked to high fatigue at the beginning of and over the course of treatment.ConclusionsThere is considerable variability in the experience of fatigue among women with early-stage breast cancer. Although the majority of women report relatively low fatigue, those with a history of depression and elevated psychological distress may be at risk of more severe and persistent fatigue.

Despite growing public and scientific interest in the positive benefits of prosociality, there has been little research on the causal effects of performing kind acts for others on psychological well-being during adolescence. Developmental changes during adolescence, such as greater perspective taking, can promote prosociality. It was hypothesized that performing kind acts for others would improve adolescent well-being (positive and negative affect, perceived stress) and increase prosocial giving. As part of a randomized controlled trial, 97 adolescents (Mage = 16.224, SD = 0.816, range 14-17; 53.608% female) were assigned to either perform kind acts for others (Kindness to Others, N = 33), perform kind acts for themselves (Kindness to Self, N = 34), or report on daily activities (Daily Report, N = 30) three times per week for four weeks. Well-being factors were measured weekly and giving was tested post-intervention. Overall, changes over time in well-being did not differ across conditions. However, altruism emerged as a significant moderator such that altruistic adolescents in the Kindness to Others condition showed increased positive affect, decreased negative affect, and decreased stress. Increased positive affect was also linked to greater prosocial giving for Kindness to Others adolescents. These findings identify individual differences that may shape the effects of doing kind acts for others on well-being during adolescence.

Inflammation has been shown to predict depression, but sensitivity to inflammation varies across individuals. Experimental studies administering potent pro-inflammatory agents have begun to characterize this sensitivity. However, risk factors for inflammation-associated depression in naturalistic contexts have not been determined. The present study examined key psychological and behavioral risk factors (state anxiety, perceived stress, negative affect, disturbed sleep, and childhood adversity) as potential moderators of the relationship between inflammation and depressive symptoms in a prospective longitudinal study of breast cancer survivors. Women with early stage breast cancer were recruited after completing primary cancer treatment (nfinal = 161). Depressive symptoms, inflammatory markers (CRP, IL-6, and sTNF-RII), and key risk factors were assessed post treatment (T1), at 6 and 12-month follow-ups (T2 and T3), and during a final follow-up (TF) 3-6 years after T1; childhood adversity was measured only at T3. Inflammatory markers were combined into a single inflammatory index prior to analyses. Women who reported higher levels of state anxiety, perceived stress, negative affect, and/or sleep disturbance at T1 (post-treatment) exhibited higher depressive symptoms at times when inflammation was higher than typical (interaction βs ranged from .06 to .08; all ps

BackgroundChildhood adversity is reliably associated with immune alterations in adulthood, including increases in inflammatory processes. However, relatively few studies have investigated these associations in clinical populations such as cancer patients who are at risk for negative immune-related health outcomes. The current study tested the hypothesis that childhood maltreatment would be associated with alterations in immune-related gene expression in monocytes from women with breast cancer.MethodsWomen (n = 86) were recruited after diagnosis with early-stage breast cancer but before onset of adjuvant therapy with radiation, chemotherapy, and/or endocrine therapy. Participants completed questionnaires to assess childhood maltreatment (Childhood Trauma Questionnaire; CTQ) and depressive symptoms (Center for Epidemiologic Studies Depression Scale; CES-D) and provided blood samples for immune assessment. CD14+ monocytes were isolated for RNA extraction and gene expression analyses.ResultsBased on responses to the CTQ, 28% of participants were classified as experiencing physical and/or emotional abuse or neglect and 7% as experiencing sexual abuse. Genome-wide transcriptional profiling of isolated monocytes identified 202 gene transcripts that differed in average expression level by > 25% over the range of maltreatment exposure. Bioinformatics analyses of those gene transcripts identified a significantly greater prevalence of NF-κB-binding motifs within the promoters of up-regulated vs. down-regulated genes (p = .028) in women exposed to childhood maltreatment, indicating greater inflammatory signaling. Parallel analyses of Type I interferon signaling also indicated greater prevalence of Interferon Response Factor (IRF)-related binding sites in women with a childhood maltreatment history (p = .020). Results remained significant in analyses controlling for current depression; however, NF-κB and IRF-related gene expression was higher in women with both maltreatment exposure and current depression.ConclusionsIn women recently diagnosed with early-stage breast cancer, childhood maltreatment was associated with increases in the classical NF-kB-related pro-inflammatory signaling pathway and with increases in the Type I interferon system. These results suggest a broad pattern of chronic immunologic activation in breast cancer patients with a history of childhood maltreatment, particularly those who are currently experiencing clinically significant depressive symptoms. These findings have implications for the long-term health and well-being of maltreatment exposed breast cancer patients.

Chronic stress can accelerate biological aging, offering one mechanism through which stress may increase age-related disease risk. Chronic activation of the sympathoadrenal system increases cellular energy production, resulting in cell stress that can initiate cellular senescence, a permanent state of cell growth arrest. Our previous research linked psychosocial stress with increased expression of senescence marker p16INK4a; however, less is known about the role of protective psychosocial factors in biological aging. We examined relationship closeness (perceived interconnectedness with one's spouse) as a protective buffer of the effects of stress on expression of the p16INK4a-encoding gene (CDKN2A) and transcription control pathways activated under cell stress. Seventy parents (Mage=43.2) completed interview-based and questionnaire measures of psychosocial stress and relationship closeness. Blood samples assessed CDKN2A expression and inferred activity of a priori-selected transcription factors Nrf2 and heat shock factors (HSFs) via genome-wide transcriptome profiling. Random intercept models adjusting for age, sex, and ethnicity/race revealed that perceived stress was associated with elevated CDKN2A expression for parents with low but not high closeness. Secondary bioinformatics analyses linked the interaction of perceived stress and relationship closeness to Nrf2 and HSF-1 activity. Findings identify relationship closeness as a protective factor that may buffer the impact of stress on cellular stress and senescence pathways.

The purpose of this study was to characterize the association between recent major life events and depressive symptoms during early adulthood, and to determine whether adolescents with chronically low positive affect or persistent sleep disturbance were more vulnerable to the link between stress and depressive symptoms. Adolescents (n = 147; 63.9% female; 33.7% non-Hispanic white) were recruited in 10th-11th grade and re-assessed 2 and 4 years later. At each assessment, adolescents completed measures of positive affect and sleep disturbances. At the final assessment, participants reported on their exposure to major life events in the past 12 months. Exposure to more major life events in the past year was associated with greater depressive symptoms in early adulthood. Chronically low positive affect and persistent sleep disturbances throughout adolescence each independently moderated this relationship. Specifically, only participants reporting low positive affect across the three assessments showed a positive and significant association between major life events and depressive symptoms. Further, only participants reporting sleep disturbances at all three assessments showed a positive and significant association between major life events and depressive symptoms. Chronically low positive affect and persistent sleep disturbances during adolescence may be useful indicators of risk for depression during early adulthood. Further, interventions targeting adolescent sleep disturbances and improving positive affect may be useful in reducing the risk for depression following life stress during this high risk developmental phase.

ProblemAltered maternal immune function predicts risk for shorter gestation and low birthweight. Few studies examine associations between prenatal immune cell gene expression and gestational length or birthweight. No studies examine which cell types drive associations. The purpose of this study is to explore associations between peripheral blood immune cell gene expression and gestational length and birthweight, using transcript origin analysis.Method of studyEighty-nine women were drawn from the Community Child Health Network cohort. Third trimester maternal dried blood spots were used for genome-wide transcriptional (mRNA) profiling. Gestational length and birthweight were obtained from medical charts. Covariates were age, race/ethnicity, pre-pregnancy body mass index, smoking, gestational age at blood sampling, and pregnancy infections. Associations between gene expression profiles and gestational length and birthweight were tested using general linear models. The Transcription Element Listening System (TELiS) bioinformatics analysis quantified upstream transcription factor activity. Transcript origin analysis identified leukocyte subsets mediating observed effects.ResultsShorter gestation was predicted by increased NF-kB (TFBM ratio = -0.582 ± 0.172, P

Systemic inflammation is associated with increasing age. Yet, there are limited data about the association between age and systemic inflammation within older adults, and whether older age is also associated with cellular and nuclear signaling markers of inflammation. In community-dwelling older adults (N = 262, 60-88 years), systemic levels of C-reactive protein, interleukin-6, and soluble tumor necrosis factor receptor II; levels of toll-like receptor-4-stimulated monocytic production of interleukin-6 and tumor necrosis factor α; and resting nuclear levels of activated nuclear factor kappa B and signal transducer and activator of transcription (STAT1, STAT3, STAT5) were evaluated. Adjusting for demographic and clinical factors, multivariate linear regression tested the association between age and each inflammatory marker. Age was positively associated with increased levels of interleukin-6 and soluble tumor necrosis factor receptor II (p's < .05) and with increases in STAT1, STAT3, and STAT5 activation (p's < .05). However, no relationship was found between age and C-reactive protein, toll-like receptor-4-stimulated interleukin-6/tumor necrosis factor alpha α production, or nuclear factor kappa B. Within a community-dwelling sample of older adults, older age is associated with increases in STAT activation, along with increases of systemic inflammatory cytokines. In older adults, heterogeneity in age-related increases in inflammatory disease risk may be related to individual variability in inflammation.

The experiences of mothers and fathers are different in ways that could affect their well-being. Yet few studies have comprehensively examined gender differences in parents' well-being. In the current research, we investigated such gender differences in a large representative sample (Study 1a; N = 13,007), in a community sample using validated well-being measures (Study 1b; N = 472), and in a large experience sampling study measuring happiness during caregiving activities and during interactions with children (Study 2; N = 4,930). Fathers reported greater happiness, subjective well-being, psychological need satisfaction, and daily uplifts than did men without children (Studies 1a and 1b). During caregiving experiences, fathers reported greater happiness, whereas mothers reported lower happiness, compared with their other activities. Fathers also reported relatively higher happiness when interacting with their children than did mothers (Study 2). Across all three studies and more than 18,000 participants, parenthood was associated with more positive well-being outcomes for fathers than for mothers.

BackgroundRates of depression increase and peak during late adolescence and alterations in immune processes are thought to be both a risk factor and outcome of depression. However, few studies have examined depression-immune dynamics among adolescents. Using a functional genomics approach, the current study examined whether depressive symptoms were associated with activation of a gene expression profile, characterized by upregulated expression of pro-inflammatory-related genes and downregulated expression of antiviral-related genes in a sample of older adolescents (Mage = 18.37, SD = 0.51).MethodParticipants (n = 87) reported on their depressive symptoms during the past week using the CES-D, and provided blood samples for genome-wide transcriptional profiling of mRNA.ResultsAdolescents with clinically-significant levels of depressive symptoms (CES-D ≥ 16) exhibited upregulated expression of inflammation-related genes and downregulated expression of antiviral-related genes compared to their peers with lower levels of depressive symptoms (CES-D

At the M2 terminal of the macrophage activation spectrum, expression of genes is regulated by transcription factors that include STAT6, CREB, and C/EBPβ. Signaling through β-adrenergic receptors drives M2 activation of macrophages, but little is known about the transcription factors involved. In the present study, we found that C/EBPβ regulates the signaling pathway between β-adrenergic stimulation and expression of Arg1 and several other specific genes in the greater M2 transcriptome. β-adrenergic signaling induced Cebpb gene expression relatively early with a peak at 1 h post-stimulation, followed by peak Arg1 gene expression at 8 h. C/EBPβ transcription factor activity was elevated at the enhancer region for Arg 1 at both 4 and 8 h after stimulation but not near the more proximal promoter region. Knockdown of Cebpb suppressed the β-adrenergic-induced peak in Cebpb gene expression as well as subsequent accumulation of C/EBPβ protein in the nucleus, which resulted in suppression of β-adrenergic-induced Arg1 gene expression. Analysis of genome-wide transcriptional profiles identified 20 additional M2 genes that followed the same pattern of regulation by β-adrenergic- and C/EBPβ-signaling. Promoter-based bioinformatic analysis confirmed enrichment of binding motifs for C/EBPβ transcription factor across these M2 genes. These findings pinpoint a mechanism that may be targeted to redirect the deleterious influence of β-adrenergic signaling on macrophage involvement in M2-related diseases such as cancer.

Racial disparities in health outcomes between African Americans and European Americans have been well-documented, but not fully understood. Chronic inflammation contributes to several of the diseases showing racial disparities (e.g., Human Immunodeficiency Virus [HIV]), and racial differences in stress exposure (e.g., experiences of racial discrimination) that stimulate pro-inflammatory processes that may contribute to differential health outcomes. We performed a cross-sectional bioinformatic analyses relating perceived discrimination (as measured by the Perceived Ethnic Discrimination Questionnaire [PED-Q]) to the activity of pro-inflammatory, neuroendocrine, and antiviral transcription control pathways relevant to the conserved transcriptional response to adversity (CTRA) in peripheral blood leukocytes. Subjects were 71 individuals (37 HIV-seropositive (HIV+); 34 HIV-seronegative (HIV-)) (mean age = 53 years, range 27-63), who self-identified either as African American/Black (n = 48) or European American/White (n = 23). This provided the opportunity to examine the independent effects of race and HIV, as well as the modifying role of perceived discrimination on pathways involved in CTRA. Exploratory analysis examined the interactive effects of HIV and race on pathways involved in CTRA. Relative to European Americans, African Americans showed increased activity of two key pro-inflammatory transcription control pathways (NF- кB and AP-1) and two stress-responsive signaling pathways (CREB and glucocorticoid receptor); these effects did not differ significantly as a function of HIV infection (HIV x Race interaction, all p > .10). Results suggested that differences in experiences of racial discrimination could potentially account for more than 50% of the total race-related difference in pro-inflammatory transcription factor activity. In sum, differential exposure to racial discrimination may contribute to racial disparities in health outcomes in part by activating threat-related molecular programs that stimulate inflammation and contribute to increased risk of chronic illnesses.

BACKGROUND:The conserved transcriptional response to adversity (CTRA), characterized by increased expression of proinflammatory genes and decreased expression of antiviral and antibody-related genes, is upregulated in the context of chronic adversity and distress and has been linked to cancer progression. Several studies suggest that the CTRA may also be down-regulated in association with some positive psychological states, particularly eudaimonic well-being. However, it is not clear if the link between inter-individual differences in the CTRA and eudaimonic well-being can be extended to intra-individual change. Using a standardized mindfulness-based intervention, the current study tested whether mindfulness-related increases in eudaimonic well-being related to intra-individual reduction in the CTRA in a sample of younger breast cancer survivors. METHODS:Participants were 22 women who had been diagnosed and treated for early-stage breast cancer at or before age 50 (Mage = 46.6 years) and had no evidence of active disease. Women completed self-report questionnaires and provided peripheral blood samples before and after a 6-week mindfulness meditation intervention. Regression analyses were used to quantify associations between the magnitude of change in eudaimonic well-being and the magnitude of change in the global CTRA score. RESULTS:Women reported significant increases in eudaimonic well-being and showed decreased expression of the pro-inflammatory subcomponent of the CTRA from pre- to post-intervention. The magnitude of increase in eudaimonic well-being was associated with the magnitude of decrease in the composite CTRA score, and this relationship was driven primarily by increased expression of the antiviral/antibody-related CTRA subcomponent. While the intervention was also associated with reduced depressive symptoms, there was no association between change in depressive symptoms and change in the overall CTRA composite score or either of its subcomponents. CONCLUSIONS:Results are consistent with the hypothesis that eudaimonic well-being may be an important mechanism in interventions aimed at enhancing health in vulnerable groups, and contribute to our understanding of how psychological well-being may influence physical health in cancer patients.

BackgroundPsychological stress and poor sleep are associated with a wide range of negative health outcomes, which are thought to be mediated in part by alterations in immune processes. However, the molecular bases of links among stress, sleep, and immune processes are not completely understood, particularly during adolescence when sensitivity to stress and problems with sleep tend to increase. In the current study, we investigated whether various stressors (daily stress, major life events, perceived stress), sleep indices (duration, efficiency), and their interactions (e.g., moderating effects) are associated with expression of genes bearing response elements for transcription factors that regulate inflammatory and anti-viral processes.MethodEighty-seven late adolescents completed daily checklists of their social experiences across a 15-day period and reported on their major life events during the previous year. They also completed actigraphy-based assessments of sleep quality and duration during 8 consecutive nights. An average of 5.5 months later, participants reported on their global perceptions of stress during the previous month and provided blood samples for genome-wide expression profiling of mRNA from peripheral blood mononuclear cells (PBMCs).ResultsHigher levels of daily interpersonal stress and shorter sleep duration were associated with upregulation of inflammation-related genes bearing response elements for proinflammatory transcription factor nuclear factor kappa B (NF-κB). Shorter sleep duration was also linked to downregulation of antiviral-related genes bearing response elements for interferon response factors (IRFs). Lastly, there was a significant interaction between daily stress and shorter sleep duration, such that the association between daily stress and inflammation-related gene expression was exacerbated in the context of shorter sleep duration. Results were independent of sex, ethnicity, parent education, body mass index, and smoking and alcohol history.ConclusionEveryday interpersonal stress and shortened sleep can be consequential for upstream NF-κB signaling pathways relevant to inflammatory processes during late adolescence. Notably, the occurrence of both may lead to even greater activation of NF-κB signaling.

Inflammation plays a significant role in the pathophysiology of depression. However, not all individuals exposed to inflammatory challenge develop depression, and identifying those at risk is necessary to develop targeted monitoring, prevention, and treatment strategies. Within a randomized double-blind placebo-controlled study (n = 115), we examined whether leukocyte transcriptome profiles predicted inflammation-induced depressed mood in volunteers who received low-dose intravenous endotoxin (n = 58; aged 18-50). At baseline, transcription factor (TF) activities were assessed using genome-wide transcriptional profiling of peripheral blood mononuclear cells and promoter-based bioinformatic analyses. Then, participants were administered endotoxin. Self-reported depressed mood was assessed using the Profile of Mood States. Based on extant studies linking transcriptional profiles to depressive disorder, we examined whether post-endotoxin depressed mood is predicted by baseline activity of TFs related to immune activation, sympathetic activation, and glucocorticoid insensitivity: respectively, nuclear factor kappa B (NF-kB), cAMP response element-binding protein (CREB), and glucocorticoid receptor (GR). Twenty-one participants (36%) experienced an increase in depressed mood from baseline to 2 h post endotoxin, when depressive response peaks. Bioinformatics analyses controlling for age, sex, ethnicity, body mass index, and physical sickness response revealed that post-endotoxin depressed mood was predicted by increased baseline activity of TFs related to inflammation (NF-kB) and beta-adrenergic signaling (CREB) and by decreased activity of GR-related TFs (P's

Previous research has linked exposure to adverse social conditions with DNA damage and accelerated telomere shortening, raising the possibility that chronic stress may impact biological aging pathways, ultimately increasing risk for age-related diseases. Less clear, however, is whether these stress-related effects extend to additional hallmarks of biological aging, including cellular senescence, a stable state of cell cycle arrest. The present study aimed to investigate associations between psychosocial stress and two markers of cellular aging-leukocyte telomere length (LTL) and cellular senescence signal p16INK4a. Seventy-three adults (Mage = 43.0, SD = 7.2; 55% female) with children between 8-13 years of age completed interview-based and questionnaire measures of their exposures to and experiences of stress, as well as daily reports of stress appraisals over an 8-week diary period. Blood samples were used to assess markers of cellular aging: LTL and gene expression of senescent cell signal p16INK4a (CDKN2A). Random effects models covarying for age, sex, ethnicity/race, and BMI revealed that participants with greater chronic stress exposure over the previous 6 months (b = 0.011, p =  .04), perceived stress (b = 0.020, p

ObjectiveCardiovascular disease (CVD) is one of the most prevalent chronic conditions and leading causes of death. Although CVD clinically manifests in adulthood, underlying processes of CVD begin in the earlier decades of life. Inflammation has been shown to play a key role, but relatively little is understood about how inflammation changes over time among young individuals. Additionally, how psychosocial factors like stress may influence changes in inflammation earlier in the lifespan is not entirely clear. Thus, the current three-wave longitudinal study examined the developmental trajectory of CRP, a marker of systemic inflammation, over a 4-year period from mid-adolescence into young adulthood. Between- and within-person differences in stress in relation to changes in CRP were also examined.MethodA sample of 350 individuals was recruited during mid-adolescence and participated in 1 to 3 assessments, 2 years apart. At each assessment, participants provided dried blood spots for the assessment of CRP and reported on recent major life events, perceived stress, and daily interpersonal stress.ResultsMultilevel modeling indicated that CRP increased with age, and within-person increases in perceived stress, but not life events or daily stress, were associated with higher CRP. Between-person differences in average levels of stress from mid-adolescence into young adulthood were not associated with changes in CRP.ConclusionThese findings suggest that the link between stress and systemic inflammation between mid-adolescence and young adulthood may be most affected by contemporaneous experiences of perceived stress. There was little evidence to suggest that CRP trajectories varied by between-person differences in overall average levels of perceived stress, life events, and daily stress. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

BackgroundFatigue is one of the most common and disabling side effects of cancer and its treatment. Although research typically has focused on fatigue that occurs during and after treatment, patients may experience fatigue even before treatment onset. The current study was designed to identify biobehavioral risk factors associated with fatigue before adjuvant therapy in women with early-stage breast cancer.MethodsPatients with stage 0 to stage IIIA breast cancer (270 women) were recruited before the onset of adjuvant or neoadjuvant therapy with radiotherapy, chemotherapy, and/or endocrine therapy. Host factors that may influence fatigue were identified from an empirically based, biobehavioral model and assessed using self-report questionnaires, medical record review, and blood collection (for genetic data). Fatigue was assessed by questionnaire. Linear regression analyses were used to evaluate the association between host factors and dimensions of fatigue, with general fatigue as the primary dimension of interest.ResultsFatigue was elevated at the pretreatment assessment compared with published controls. Bivariate analyses identified demographic, cancer-related, and biobehavioral correlates of fatigue. In the multivariable model, predictors of general fatigue included younger age, lower educational level, lower cancer stage, and history of childhood maltreatment (all P values

BackgroundStress exposure is associated with risk for adverse pregnancy outcomes, potentially in part through dysregulated immune and inflammatory activity. Evidence suggests that stress during pregnancy is associated with inflammation during pregnancy, consistent with risk for preterm birth. However, research has not tested whether complementary changes are reflected in immune cell gene expression, or upstream regulation of inflammation. The purpose of this study was to test associations between preconception and prenatal stress exposure and third trimester immune cell gene expression, focusing specifically on sets of genes previously linked to stress in non-pregnant samples: Pro-inflammatory genes, and antiviral and antibody genes.MethodsA sample of 116 low-income, diverse women was recruited from 5 U.S. sites by the Community Child and Health Network at the birth of a child. This study is of the subgroup of women who became pregnant again over the two-year follow-up period, and provided information on stressful life events that occurred both preconception and during the third trimester of the subsequent pregnancy. Dried blood spots (DBS) were collected in the third trimester of pregnancy, and used for gene expression analysis.ResultsWomen with more prenatal stressful life events had higher expression of pro-inflammatory genes when compared to those with fewer life events, and the effect was driven by increased activation of pro-inflammatory transcription factors, NF-κB and AP-1. Preconception stressful life event exposure was not associated with gene expression profiles. When entered into models simultaneously, only prenatal stressful life events were associated with up-regulation of pro-inflammatory genes. No differences between high or low stress groups emerged for antiviral or antibody genes.ConclusionsPrenatal stress exposure was associated with up-regulated pro-inflammatory gene expression during pregnancy, and increased activity of NF-κB and AP-1. In contrast, stress occurring preconception was not associated with gene expression. These results are consistent with the hypothesis that stress-induced activation of pro-inflammatory transcriptional pathways in pregnancy, but not earlier, may increase risk for inflammation-driven adverse pregnancy outcomes.

ObjectiveFatigue is a common side effect of cancer treatment, but there is considerable variability in fatigue severity and persistence among survivors. This study aimed to characterize longitudinal trajectories of fatigue after breast cancer treatment and to identify predictors of varying fatigue trajectories.MethodsWomen (N = 191) from the Mind-Body Study completed assessments after primary treatment for early stage breast cancer and at regular follow-ups that occurred up to 6 years after treatment (M = 4.3 years). Growth mixture models were used to characterize fatigue trajectories, and demographic, medical, and biobehavioral risk factors were examined as predictors of trajectory group.ResultsFive trajectories were identified, characterized as High, Recovery, Late, Low, and Very Low fatigue. The High and Recovery groups (40% of sample) evidenced elevated fatigue at posttreatment that declined in Recovery but persisted in the High group. In bivariate analyses, trajectory groups differed significantly on depressive symptoms, sleep disturbance, childhood adversity, body mass index, and the inflammatory marker soluble TNF receptor type II, which were higher in the High and/or Recovery groups. In multivariate models, depressive symptoms and childhood adversity distinguished High and Recovery from other groups. Rates of chemotherapy were higher in the Recovery than in the High or Late group, whereas rates of endocrine therapy were higher in the High than in the Recovery group.ConclusionsThere are distinct longitudinal trajectories of fatigue after breast cancer treatment. Psychological factors are strongly associated with adverse fatigue trajectories, and together with treatment exposures may increase risk for cancer-related fatigue. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Adverse social conditions have been linked to a conserved transcriptional response to adversity (CTRA) in circulating leukocytes that may contribute to social gradients in disease. However, the CNS mechanisms involved remain obscure, in part because CTRA gene-expression profiles often track external social-environmental variables more closely than they do self-reported internal affective states such as stress, depression, or anxiety. This study examined the possibility that variations in patterns of natural language use might provide more sensitive indicators of the automatic threat-detection and -response systems that proximally regulate autonomic induction of the CTRA. In 22,627 audio samples of natural speech sampled from the daily interactions of 143 healthy adults, both total language output and patterns of function-word use covaried with CTRA gene expression. These language features predicted CTRA gene expression substantially better than did conventional self-report measures of stress, depression, and anxiety and did so independently of demographic and behavioral factors (age, sex, race, smoking, body mass index) and leukocyte subset distributions. This predictive relationship held when language and gene expression were sampled more than a week apart, suggesting that associations reflect stable individual differences or chronic life circumstances. Given the observed relationship between personal expression and gene expression, patterns of natural language use may provide a useful behavioral indicator of nonconsciously evaluated well-being (implicit safety vs. threat) that is distinct from conscious affective experience and more closely tracks the neurobiological processes involved in peripheral gene regulation.

ContextProsocial behavior is linked to longevity, but few studies have experimentally manipulated prosocial behavior to identify the causal mechanisms underlying this association. One possible mediating pathway involves changes in gene expression that may subsequently influence disease development or resistance.Design, setting, participantsIn the current study, we examined changes in a leukocyte gene expression profile known as the Conserved Transcriptional Response to Adversity (CTRA) in 159 adults who were randomly assigned for 4 weeks to engage in prosocial behavior directed towards specific others, prosocial behavior directed towards the world in general, self-focused kindness, or a neutral control task.ResultsThose randomized to prosocial behavior towards specific others demonstrated improvements (i.e., reductions) in leukocyte expression of CTRA indicator genes. No significant changes in CTRA gene expression were observed in the other 3 conditions.ConclusionThese findings suggest that prosocial behavior can causally impact leukocyte gene expression profiles in ways that might potentially help explain the previously observed health advantages associated with social ties.

β-Adrenergic signaling can regulate macrophage involvement in several diseases and often produces anti-inflammatory properties in macrophages, which are similar to M2 properties in a dichotomous M1 vs. M2 macrophage taxonomy. However, it is not clear that β-adrenergic-stimulated macrophages may be classified strictly as M2. In this in vitro study, we utilized recently published criteria and transcriptome-wide bioinformatics methods to map the relative polarity of murine β-adrenergic-stimulated macrophages within a wider M1-M2 spectrum. Results show that β-adrenergic-stimulated macrophages did not fit entirely into any one pre-defined category of the M1-M2 spectrum but did express genes that are representative of some M2 side categories. Moreover, transcript origin analysis of genome-wide transcriptional profiles located β-adrenergic-stimulated macrophages firmly on the M2 side of the M1-M2 spectrum and found active suppression of M1 side gene transcripts. The signal transduction pathways involved were mapped through blocking experiments and bioinformatics analysis of transcription factor binding motifs. M2-promoting effects were mediated specifically through β2-adrenergic receptors and were associated with CREB, C/EBPβ, and ATF transcription factor pathways but not with established M1-M2 STAT pathways. Thus, β-adrenergic-signaling induces a macrophage transcriptome that locates on the M2 side of the M1-M2 spectrum but likely accomplishes this effect through a signaling pathway that is atypical for M2-spectrum macrophages.

BackgroundInflammation contributes to the development of depression in a subset of individuals, but risk factors that render certain individuals particularly vulnerable to inflammation-associated depression are undetermined. Drawing from animal studies showing that reduced neuroplasticity mediates effects of inflammation on depression, we hypothesized that individuals genetically predisposed to lower levels of neuroplasticity would be more susceptible to inflammation-associated depression. The current study examined whether the Met allele of the BDNF Val66met polymorphism, which predisposes individuals to reduced levels of brain-derived neurotrophic factor (BDNF), a protein vital for neuroplasticity, moderates the association between inflammation and depressive symptoms.MethodsOur sample was 112 women with early-stage breast cancer who had recently completed cancer treatment, which can activate inflammation. Participants provided blood for genotyping and assessment of circulating inflammatory markers, and completed a questionnaire assessing depressive symptoms, including somatic, affective, and cognitive dimensions.ResultsThere was a significant interaction between C-reactive protein (CRP) and the BDNF Val66met polymorphism in predicting cognitive depressive symptoms (p=.004), such that higher CRP was related to more cognitive depressive symptoms among Met allele carriers, but not among Val/Val homozygotes. Post-hoc longitudinal analyses suggested that, for Met carriers, higher CRP at baseline predicted higher cognitive depressive symptoms across a one-year follow-up period (p

BackgroundPremenopausal women diagnosed with breast cancer are at risk for psychological and behavioral disturbances after cancer treatment. Targeted interventions are needed to address the needs of this vulnerable group.MethodsThis randomized trial provided the first evaluation of a brief, mindfulness-based intervention for younger breast cancer survivors designed to reduce stress, depression, and inflammatory activity. Women diagnosed with early stage breast cancer at or before age 50 who had completed cancer treatment were randomly assigned to a 6-week Mindful Awareness Practices (MAPS) intervention group (n = 39) or to a wait-list control group (n = 32). Participants completed questionnaires before and after the intervention to assess stress and depressive symptoms (primary outcomes) as well as physical symptoms, cancer-related distress, and positive outcomes. Blood samples were collected to examine genomic and circulating markers of inflammation. Participants also completed questionnaires at a 3-month follow-up assessment.ResultsIn linear mixed models, the MAPS intervention led to significant reductions in perceived stress (P = .004) and marginal reductions in depressive symptoms (P = .094), as well as significant reductions in proinflammatory gene expression (P = .009) and inflammatory signaling (P = .001) at postintervention. Improvements in secondary outcomes included reduced fatigue, sleep disturbance, and vasomotor symptoms and increased peace and meaning and positive affect (P

Experimental studies in preclinical mouse models of breast cancer have shown that chronic restraint stress can enhance disease progression by increasing catecholamine levels and subsequent signaling of β-adrenergic receptors. Catecholamines also signal α-adrenergic receptors, and greater α-adrenergic signaling has been shown to promote breast cancer in vitro and in vivo. However, antagonism of α-adrenergic receptors can result in elevated catecholamine levels, which may increase β-adrenergic signaling, because pre-synaptic α2-adrenergic receptors mediate an autoinhibition of sympathetic transmission. Given these findings, we examined the effect of α-adrenergic blockade on breast cancer progression under non-stress and stress conditions (chronic restraint) in an orthotopic mouse model with MDA-MB-231HM cells. Chronic restraint increased primary tumor growth and metastasis to distant tissues as expected, and non-selective α-adrenergic blockade by phentolamine significantly inhibited those effects. However, under non-stress conditions, phentolamine increased primary tumor size and distant metastasis. Sympatho-neural gene expression for catecholamine biosynthesis enzymes was elevated by phentolamine under non-stress conditions, and the non-selective β-blocker propranolol inhibited the effect of phentolamine on breast cancer progression. Selective α2-adrenergic blockade by efaroxan also increased primary tumor size and distant metastasis under non-stress conditions, but selective α1-adrenergic blockade by prazosin did not. These results are consistent with the hypothesis that α2-adrenergic signaling can act through an autoreceptor mechanism to inhibit sympathetic catecholamine release and, thus, modulate established effects of β-adrenergic signaling on tumor progression-relevant biology.

BackgroundYoga is a popular mind-body therapy that has demonstrated beneficial effects on psychological, behavioral, and functional outcomes. However, few studies have investigated effects on inflammatory processes. This study tested the hypothesis that an Iyengar yoga intervention specifically designed for fatigued breast cancer survivors would lead to decreases in inflammation-related gene expression and circulating markers of proinflammatory cytokine activity.MethodsBreast cancer survivors with persistent cancer-related fatigue were randomized to a 12-week Iyengar yoga intervention (n=16) or a 12-week health education control condition (n=15). Blood samples were collected at baseline, post-intervention, and at a 3-month follow-up for genome-wide transcriptional profiling and bioinformatic analyses. Plasma inflammatory markers and salivary cortisol were also assessed.ResultsIn promoter-based bioinformatics analyses, the yoga group showed reduced activity of the pro-inflammatory transcription factor nuclear factor kappa B (NF-κB), increased activity of the anti-inflammatory glucocorticoid receptor, and reduced activity of cAMP response element-binding protein (CREB) family transcription factors relative to controls (all ps

BackgroundSocial environmental influences on human health are well established in the epidemiology literature, but their functional genomic mechanisms are unclear. The present study analyzed genome-wide transcriptional activity in people who chronically experienced high versus low levels of subjective social isolation (loneliness) to assess alterations in the activity of transcription control pathways that might contribute to increased adverse health outcomes in social isolates.ResultsDNA microarray analysis identified 209 genes that were differentially expressed in circulating leukocytes from 14 high- versus low-lonely individuals, including up-regulation of genes involved in immune activation, transcription control, and cell proliferation, and down-regulation of genes supporting mature B lymphocyte function and type I interferon response. Promoter-based bioinformatic analyses showed under-expression of genes bearing anti-inflammatory glucocorticoid response elements (GREs; p = 0.032) and over-expression of genes bearing response elements for pro-inflammatory NF-kappaB/Rel transcription factors (p = 0.011). This reciprocal shift in pro- and anti-inflammatory signaling was not attributable to differences in circulating cortisol levels, or to other demographic, psychological, or medical characteristics. Additional transcription control pathways showing differential activity in bioinformatic analyses included the CREB/ATF, JAK/STAT, IRF1, C/EBP, Oct, and GATA pathways.ConclusionThese data provide the first indication that human genome-wide transcriptional activity is altered in association with a social epidemiological risk factor. Impaired transcription of glucocorticoid response genes and increased activity of pro-inflammatory transcription control pathways provide a functional genomic explanation for elevated risk of inflammatory disease in individuals who experience chronically high levels of subjective social isolation.