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Psychosocial stress and adversity have been linked to accelerated aging and increased risk for age-related diseases. Animal and in vitro studies have shown that exposure to stress hormones (catecholamines, glucocorticoids) can impact biological aging processes such as DNA damage and cellular senescence, suggesting they play a key role in links between stress and aging; however, these associations have not been well investigated in humans. We examined cross-sectional associations between chronic stress exposures, stress hormones, and biological aging markers in midlife adults and whether stress hormones mediated associations between stress and aging. Participants were 531 adults aged 26-78 years (M age  = 53.9, 50.1 % female) in the nationally representative Midlife in the United States Refresher cohort. They reported chronic stress exposures in childhood and adulthood (Stressful Life Event Inventory) and provided 12-hour urine samples used to assess norepinephrine, epinephrine, and cortisol. RNA sequencing of peripheral blood mononuclear cells derived aging biomarkers: the DNA damage response (DDR; 30-gene composite), cellular senescence signal p16 INK4a (CDKN2A), and the pro-inflammatory senescence-associated secretory phenotype (SASP; 57-gene composite). Regression models adjusting for age, sex, race/ethnicity, BMI, smoking status, alcohol use, and medications revealed that more childhood exposures were associated with higher norepinephrine (β = 0.09, p = 0.04), independent from adult exposures. Higher norepinephrine was associated with elevated DDR expression (β = 0.17, p < 0.001). Higher norepinephrine (β = 0.14, p = 0.003) and epinephrine (β = 0.10, p = 0.02) were both associated with elevated SASP expression. Statistical mediation analyses implicated elevated norepinephrine as a plausible mediator of associations between childhood exposures and both DDR (unstandardized b = 0.005, 95 % CI [0.0002, 0.011]) and SASP (b = 0.002, 95 % CI [0.0001, 0.05]). Findings provide preliminary evidence in humans that stress hormones may impact key biological aging processes and may be a mechanism linking chronic stress exposures in childhood to accelerated aging later in life., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Accumulating evidence indicates that social isolation (SI) in humans and rodents is associated with increased cancer incidence and mortality, yet mediating mechanisms remain elusive. Here, we examine the neuroendocrine and immunological consequences of SI and its short- and long-term physiological impacts in naïve and cancer-bearing rats. Findings indicate that isolated animals experienced a significant decrease in weight compared to controls. Specifically, females showed a marked weight decrease during the first week of isolation. Isolated rats had significantly higher numbers of MADB106 experimental pulmonary metastases. Although mortality rates were higher in isolated tumor-bearing rats, unexpectedly, they exhibited a reduced growth rate of orthotopically implanted MADB106 tumors. Transcriptomic analyses of these excised tumors indicated a major downregulation in the expression of various genes, including those associated with pro-metastatic processes (e.g., EMT). In naïve rats (no cancer), levels of IL-6 increased, and total IgG levels decreased under SI conditions. A mixed effect was found for TNFα, which increased in females and decreased in males. In the central nervous system, isolated rats showed altered gene expression in key brain regions associated with stress responses and social behavior. The paraventricular nucleus of the thalamus emerged as a significantly affected region, along with the bed nucleus of the stria terminalis. Changes were observed in the expression of oxytocin, serotonin, and dopamine receptors. Isolated rats also exhibited greater alterations in hypothalamic-pituitary-adrenal (HPA) axis-related regulation and an increase in plasma CORT levels. Our study highlights the profound impact of SI on metastatic processes. Additionally, the potential detrimental effects of SI on thermoregulation were discussed, emphasizing the importance of social thermoregulation in maintaining physiological stability and highlighting the need to avoid single-caging practices in research. We report neuro-immune interactions and changes in brain gene expression, highlighting the need for further research into these underlying processes to improve outcomes in animal models and potential interventions for cancer patients through increased social support., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

To address the challenge of predicting psychological response to a psychosocial intervention we tested the possibility that baseline gene expression profiles might provide information above and beyond baseline psychometric measures. The genomics strategy utilized individual level inferences of transcription factor activity to predict changes in loneliness and affect in response to two well-established meditation interventions. Initial algorithm development analyses focused on three a-priori defined stress-related gene regulation pathways (CREB, GR, and NF-ĸB) as inferred from TELiS promoter-based bioinformatic analysis of basal (pre-intervention) blood samples from a randomized-controlled trial comparing a compassion-based meditation (CM, n = 45) with mindfulness meditation (MM, n = 44). Greater baseline CREB activity (but not GR or NF-ĸB) predicted greater reductions from pre- to post-intervention in loneliness (b = -0.24, p = 0.016) and negative emotions (b = -0.23, p = 0.017) for CM, but not for MM. A second algorithm validation analysis applied the same approach to another randomized controlled trial comparing CM (n = 42) with MM (n = 38) and a health education control condition (n = 41). Similarly, greater baseline CREB activity predicted greater pre- to post-intervention decreases in loneliness (b = -0.24, p = 0.029) and greater increases in satisfaction with life (b = 0.21, p = 0.046) for the CM condition only. Baseline CREB activity was not associated with baseline psychometric measures in either study. Results raise the possibility that pre-intervention gene expression profiles may reflect non-conscious psychobiological states that affect psychological responses to distinct psychosocial interventions, and thereby help personalize intervention selection., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Background: Social isolation and loneliness (known as social disconnection, collectively) lead to serious downstream health effects, including shortening of lifespan and higher risk for cardiac disease. We must better understand how isolation and loneliness lead to these negative health outcomes. Previous literature has demonstrated that social motivation and social ability are contributors to the likelihood of social isolation and loneliness. We examined the effect of the above social factors on immune gene expression in socially-connected and -isolated individuals., Methods: Recruitment occurred via two online advertisements, one for socially isolated individuals and another for general research participants. Participants (n = 102) were separated into groups (isolated versus connected) based on which ad they responded to, and provided data on isolation, loneliness, social motivation, and social ability. The Conserved Transcriptional Response to Adversity (CTRA) stress gene regulation program was assessed with genome-wide transcriptional profiling., Results: CTRA gene expression patterns were reversed between connected and isolated groups across several variables. Social isolation was associated with higher CTRA levels in the connected group, but lower levels in the isolated group. Social approach was associated with lower CTRA levels in the connected group, but higher in the isolated group, and the converse was true for social avoidance. CTRA levels were minimally affected by social ability measures., Conclusion: Prior work on social isolation and loneliness has focused on loneliness and has identified many negative downstream health effects. In this study we demonstrate that objective social isolation may not be associated with the same negative downstream health effects, and in fact, social interaction may be more stressful than social isolation for some socially-isolated individuals., (Published by Elsevier Inc.)

Background: Insomnia contributes to inflammation in breast cancer survivors. This study evaluates whether insomnia treatment reverses inflammation in breast cancer survivors with insomnia., Methods: Participants (n = 90) were randomized to 3 months of Tai Chi (n = 45) or cognitive behavioral therapy for insomnia (CBT-I)(n = 45), and followed for one year post-intervention to 15 month endpoint. Our previous report found that Tai Chi as compared to CBT-I resulted in similar rates of insomnia response and remission over 15 months. Here, we analyze changes in plasma C-reactive protein and pro- and anti-inflammatory cytokines, Toll-like receptor (TLR)-4 stimulated monocyte production of interleukin (IL)-6 and tumor necrosis factor-α (TNF), and cellular pro-inflammatory and anti-viral gene expression (Conserved Transcriptional Response to Adversity RNA profile; CTRA) over 15 months., Results: Insomnia treatment resulted in decreases in the TLR-4 stimulated monocyte production of IL-6, TNF, and their co-expression, as well as decreases in the CTRA profile, decreases inflammatory gene transcripts, and increases in anti-viral gene transcripts over 15 months (all P's < 0.01). In addition, as compared to CBT-I, Tai Chi resulted in greater decreases in plasma IL-6 (P < 0.05), and greater decreases in TLR-4 activated monocyte production of IL-6 and co-expression of IL-6 and TNF at 15 month endpoint. CBT-I resulted in greater increases in anti-viral gene transcripts., Conclusions: Administration of either CBT-I or Tai Chi effectively treats insomnia, and shows additional benefits of reducing cellular and genomic markers of inflammation, and increasing anti-viral genomic markers in breast cancer survivors with insomnia. Tai Chi, as compared to CBT-I, yields greater and more durable decreases in systemic- and cellular inflammation. Targeting insomnia might mitigate the risk of inflammation-related co-morbidities in breast cancer survivors., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Multiple myeloma (MM) is an incurable cancer and is the leading indication for autologous hematopoietic stem cell transplantation (HSCT). To be eligible for HSCT, a patient must have a caregiver, as caregivers play a central role in HSCT preparation and recovery. MM patients remain on treatment indefinitely, and thus patients and their caregivers face long-term challenges including the intensity of HSCT and perpetual therapy after transplant. Importantly, both patients and their caregivers show heightened depressive and anxiety symptoms, with dyadic correspondence evidenced and caregivers' distress often exceeding that of patients. An extensive psychoneuroimmunology (PNI) literature links distress with health via immune and neuroendocrine dysregulation as well as biological aging. However, data on PNI in the context of multiple myeloma - in patients or caregivers - are remarkably limited. Distress in MM patients has been associated with poorer outcomes including higher inflammation, greater one year post-HSCT hospital readmissions, and worse overall survival. Further, anxiety and depression are linked to biological aging and may contribute to the poor long-term health of both patients and caregivers. Because MM generally affects older adults, individual differences in biological aging may represent an important modifier of MM biology and HSCT treatment outcomes. There are a number of clinical scenarios in which biologically younger people could be prescribed more intensive therapies, with potential for greater benefit, by using a personalized cancer therapy approach based on the quantification of physiologic reserve. Further, despite considerable psychological demands, the effects of distress on health among MM caregivers is largely unexamined. Within this context, the current critical review highlights gaps in knowledge at the intersection of HSCT, inflammation, and biological aging in the context of MM. Research in this area hold promise for opportunities for novel and impactful psychoneuroimmunology (PNI) research to enhance health outcomes, quality of life, and longevity among both MM patients and their caregivers., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Marital quality shares ties to inflammatory conditions like cardiovascular disease and diabetes. For decades, research has focused on marital conflict as a primary mechanism given its potential to trigger inflammatory responses. However, longitudinal evidence suggests that marital conflict declines over time, and little attention has been paid to the inflammatory aftermath of other types of marital exchanges. A spouse's emotional distress is an important but overlooked marital context, as partners are exposed to each other's upsetting emotions throughout adulthood. To directly compare reactivity in proinflammatory gene expression to these two marital stressors and to examine differences by age and marital satisfaction, 203 community adults ages 25-90 (N = 102 couples) provided blood samples and rated their negative mood before and after they 1) watched their partner relive an upsetting personal memory and, in a separate visit 1-2 weeks later, 2) discussed a conflictual topic in their relationship. Controlling for age, sex, race/ethnicity, BMI, alcohol use, smoking, and comorbidities, increases in proinflammatory gene expression were significantly larger after the partner's upsetting disclosure than after marital conflict (B = 0.073, SE = 0.031, p = .018). This pattern paralleled emotional reactivity to the tasks, wherein negative mood rose more in response to the partner's disclosure than to marital conflict (B = 4.305, SE = 1.468, p = .004). In sum, proinflammatory and mood reactivity to spousal distress exceeded reactivity to marital conflict, a well-established marital stressor. Findings reveal spousal distress as a novel mechanism that may link marriage to inflammation-related diseases, and even pose risks for both happy and unhappy couples across adulthood., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Fatigue is a common side effect of cancer and its treatment and is thought to be driven in part by activation of the proinflammatory cytokine network. However, the cellular and molecular underpinnings of cancer-related fatigue (CRF) have not been determined, nor have immune pathways beyond inflammation been carefully investigated. The goal of this study was to examine the association between CRF and activation of canonical proinflammatory gene regulation pathways and Type I interferon (IFN) signaling pathways in breast cancer patients during and after treatment., Methods: Women diagnosed with early-stage breast cancer (n = 181) completed assessments before and after treatment with radiation and/or chemotherapy and at 6, 12, and 18-month post-treatment follow-ups. Assessments included self-reported fatigue (Multidimensional Fatigue Symptom Inventory - Short Form) and expression of pre-specified sets of Type I IFN and pro-inflammatory immune response genes determined from mRNA sequencing of PBMCs. Mixed effect linear models examined changes in fatigue and immune gene expression over time and tested the hypothesis that fatigue would be associated with increased expression of Type I IFN and inflammatory response genes., Results: There were significant changes in fatigue and immune gene expression across the assessment period; all measures increased from pre- to post-treatment but showed diverging patterns over the follow-up, with declines in fatigue and persistent elevations in Type I IFN and proinflammatory gene expression. In mixed effect linear models, expression of Type I IFN response genes was elevated in association with fatigue across the assessment period, from pre-treatment to 18-month follow-up. In contrast, pro-inflammatory gene expression was associated with fatigue only at 6, 12, and 18-month follow-ups. Analyses controlling for changes in leukocyte subsets continued to show a significant association between fatigue and Type I IFN gene expression but reduced the time-dependent association with pro-inflammatory gene expression to non-significant., Conclusions: Results revealed unexpected complexity in the immune underpinnings of CRF and identify a novel role for IFN signaling as a robust contributor to this symptom before, during, and after treatment. Pro-inflammatory gene expression emerged as a predictor of fatigue later in the cancer trajectory, and that effect was primarily accounted for by a concurrent increase in monocyte prevalence., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Perioperative stress and inflammatory signaling can invigorate pro-metastatic molecular processes in patients' tumors, potentially worsening long-term survival. Yet, it is unknown whether pre-operative psychotherapeutic interventions can attenuate such effects. Herein, three weeks before surgery, forty women diagnosed with stage I-III invasive ductal/lobular breast carcinoma were randomized to a 6-week one-on-one psychological intervention (6 meetings with a medical psychologist and bi-weekly phone calls) versus standard nursing-staff-attention. The intervention protocol was individually tailored based on evaluation of patients' emotional, cognitive, physiological, and behavioral stress response-patterns, and also included psychoeducation regarding medical treatments and recruitment of social support. Resected primary tumors were subjected to whole-genome RNA sequencing and bioinformatic analyses, assessing a priori hypothesized cancer-relevant molecular signatures. Self-report questionnaires (BSI-18, Hope-18, MSPSS, and a stress-scale) were collected three (T1) and one (T2) week before surgery, a day before (T3) and after (T4) surgery, and three weeks (T5) and 3-months (T6) following surgery. The intervention reduced distress (GSI), depression, and somatization scores (BSI-18: p < 0.01, p < 0.05, p < 0.05; T5 vs. T1). Additionally, tumors from treated patients (vs. controls) showed: (i) decreased activity of transcription control pathways involved in adrenergic and glucocorticoid signaling (CREB, GR) (p < 0.001), pro-inflammatory signaling (NFkB) (p < 0.01), and pro-malignant signaling (ETS1, STAT and GATA families) (p < 0.001, p < 0.01, p < 0.005); (ii) increased M1 macrophage polarization (p < 0.05), and CD4 + T cell activity (p < 0.01); and an unexpected increase in epithelial-to-mesenchymal-transition (EMT) signature (p < 0.005). This is the first randomized controlled trial to show beneficial effects of a psychological perioperative intervention on tumor pro-metastatic molecular biomarkers., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Growing evidence suggests that social relationship quality can influence age-related health outcomes, although how the quality of one's relationships directly relates to the underlying aging process is less clear. We hypothesized that the absence of close relationships as well as lower support and higher strain within existing relationships would be associated with an accelerated epigenetic aging profile among older adults in the Health and Retirement Study. Adults (N = 3,647) aged 50-100 years completed ratings of support and strain in relationships with their spouse, children, other family members, and friends. They also provided a blood sample that was used for DNA methylation profiling to calculate a priori-specified epigenetic aging measures: Horvath, Hannum, PhenoAge, GrimAge, and Dunedin Pace of Aging methylation (DunedinPoAm38). Generalized linear models that adjusted for chronological age, sex, and race/ethnicity and applied a false discovery rate correction revealed that the absence of marital and friend relationships related to an older GrimAge and faster DunedinPoAm38. Among those with existing relationships, lower support from a spouse, child, other family, and friends and higher strain with friends related to an older PhenoAge and GrimAge and faster DunedinPoAm38. In secondary analyses that further adjusted for socioeconomic and lifestyle factors, lower support from other family members and friends was associated with greater epigenetic aging. Findings suggest that the absence of close relationships and lower support within existing relationships-particularly with family members and friends-relate to accelerated epigenetic aging in older adulthood, offering one mechanism through which social relationships might influence risk for age-related declines and disease., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

As an arousal hub region in the brain, the locus coeruleus (LC) has bidirectional connections with the autonomic nervous system. Magnetic resonance imaging (MRI)-based measures of LC structural integrity have been linked to cognition and arousal, but less is known about factors that influence LC structure and function across time. Here, we tested the effects of heart rate variability (HRV) biofeedback, an intervention targeting the autonomic nervous system, on LC MRI contrast and sympathetic activity. Younger and older participants completed daily HRV biofeedback training for five weeks. Those assigned to an experimental condition performed biofeedback involving slow, paced breathing designed to increase heart rate oscillations, whereas those assigned to a control condition performed biofeedback to decrease heart rate oscillations. At the pre- and post-training timepoints, LC contrast was assessed using turbo spin echo MRI scans, and RNA sequencing was used to assess cAMP-responsive element binding protein (CREB)-regulated gene expression in circulating blood cells, an index of sympathetic nervous system signaling. We found that left LC contrast decreased in younger participants in the experimental group, and across younger participants, decreases in left LC contrast were related to the extent to which participants increased their heart rate oscillations during training. Furthermore, decreases in left LC contrast were associated with decreased expression of CREB-associated gene transcripts. On the contrary, there were no effects of biofeedback on LC contrast among older participants in the experimental group. These findings provide novel evidence that in younger adults, HRV biofeedback involving slow, paced breathing can decrease both LC contrast and sympathetic nervous system signaling., Competing Interests: Declaration of competing interest None., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Discrimination is associated with negative health outcomes as mediated in part by chronic stress, but a full understanding of the biological pathways is lacking. Here we investigate the effects of discrimination involved in dysregulating the brain-gut microbiome (BGM) system., Methods: A total of 154 participants underwent brain magnetic resonance imaging to measure functional connectivity. Fecal samples were obtained for 16S ribosomal RNA profiling and fecal metabolites and serum for inflammatory markers, along with questionnaires. The Everyday Discrimination Scale was administered to measure chronic and routine experiences of unfair treatment. A sparse partial least squares-discriminant analysis was conducted to predict BGM alterations as a function of discrimination, controlling for sex, age, body mass index, and diet. Associations between discrimination-related BGM alterations and psychological variables were assessed using a tripartite analysis., Results: Discrimination was associated with anxiety, depression, and visceral sensitivity. Discrimination was associated with alterations of brain networks related to emotion, cognition and self-perception, and structural and functional changes in the gut microbiome. BGM discrimination-related associations varied by race/ethnicity. Among Black and Hispanic individuals, discrimination led to brain network changes consistent with psychological coping and increased systemic inflammation. For White individuals, discrimination was related to anxiety but not inflammation, while for Asian individuals, the patterns suggest possible somatization and behavioral (e.g., dietary) responses to discrimination., Conclusions: Discrimination is attributed to changes in the BGM system more skewed toward inflammation, threat response, emotional arousal, and psychological symptoms. By integrating diverse lines of research, our results demonstrate evidence that may explain how discrimination contributes to health inequalities., (Copyright © 2022 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Early life adversity (ELA) has long been associated with increased risk for stress-related psychopathology, particularly depression. The neuroimmune network hypothesis posits that ELA increases sensitivity to psychosocial stress, moderating the association between increases in peripheral markers of inflammation and decreases in reward outcomes linked to anhedonia and risk-taking behaviors. The present study examined this hypothesis in a sample of adolescents by using acute psychosocial stress to probe the role of inflammatory signaling in behavioral measures of reward and risk processing., Method: 80 adolescents [13.86 years (SD = 1.54); 45 % female], oversampled for ELA, underwent the Trier Social Stress Test for Children while providing blood samples immediately before and 60-minutes after stress onset. Blood samples were assayed for plasma IL-6. One hour before stress onset, and then 60 min after, participants completed computer-administered behavioral tasks measuring reward (Pirate Task) and risk (Balloon Analog Risk Task)., Results: ELA moderated the association between increases in IL-6 and decreases in risk tolerance in pursuit of rewards (p = 0.003) and reward response bias (p = 0.04). Stress-induced increases in IL-6 were associated with decreases in pumps for rewards among adolescents exposed to high, relative to little or no, ELA. Further, greater IL-6 increases were associated with increases in bias toward high relative to low value rewards among adolescents with low adversity exposure but not among those exposed to higher adversity., Conclusions: The present study provides the first evidence in a pediatric sample that ELA may alter the role of stress-induced inflammation in reward and risk processing, and may extend our understanding of why stress leads to depression in this high-risk population., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

We recently showed that a minimally-invasive removal of MDA-MB-231 HM primary tumors (PTs) and elimination of their secreted factors (including IL-6, IL-8, VEGF, EGF, PDGF-aa, MIF, SerpinE1, and M-CSF), caused regression of spontaneous micro-metastases into a non-growing dormant state. To explore the underlying mechanisms and potential clinical ramifications of this phenomenon, we herein used the MDA-MB-231 HM human breast cancer cell-line, in-vitro, and in vivo following orthotopic implantation in immune-deficient BALB/C nu/nu mice. Employing bioluminescence imaging, we found that adding laparotomy to minimally-invasive removal of the PT caused an outbreak of micro-metastases. However, perioperative β-adrenergic and COX-2 inhibition, using propranolol + etodolac, maintained metastatic dormancy following laparotomy. In-vitro, β-adrenergic agonists (epinephrine or metaproterenol) and prostaglandin-E2 markedly increased MDA-MB-231 HM secretion of the pro-metastatic factors IL-6, IL-8, and VEGF, whereas cortisol reduced their secretion, effects that were maintained even 12 h after the washout of these agonists. In-vivo, laparotomy elevated IL-6 and IL-8 levels in both plasma and ex-vivo PT spontaneous secretion, whereas perioperative propranolol + etodolac administration blocked these effects. Similar trends were evident for EGF and MIF. Promoter-based bioinformatics analyses of excised PT transcriptomes implicated elevated NF-kB activity and reduced IRF1 activity in the gene regulatory effects of laparotomy, and these effects were inhibited by pre-surgical propranolol + etodolac. Taken together, our findings suggest a novel mechanism of post-operative metastatic outbreak, where surgery-induced adrenergic and prostanoid signaling increase the secretion of pro-metastatic factors, including IL-6, IL-8, and VEGF, from PT and possibly residual malignant tissue, and thereby prevent residual disease from entering dormancy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Mindfulness meditation training has been shown to be an effective stress reduction strategy, but less is known about its immunoregulatory impact. In a randomized controlled trial of stressed customer service workers, the present study tested whether a 30-day smartphone-based mindfulness meditation training program (compared to a problem-solving control program) would affect pro-inflammatory gene expression. Both interventions led to reductions in stress levels, but there was no difference in stress reduction between conditions. Consistent with predictions, mindfulness training reduced activity of the pro-inflammatory NF-κB transcription control pathway compared to the active control. These results suggest that mindfulness training may be a particularly effective method for improving immune cell gene expression in stressful work environments., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Individuals exposed to persistent neighborhood violence are at increased risk for developing mental and physical health problems across the lifespan. The biological mechanisms underlying this phenomenon are not well understood. Thus, we examined the relationship between children's exposure to neighborhood violence and inflammatory activity, a process involved in the pathogenesis of multiple health problems. 236 children from the Chicago area participated in a two-year longitudinal study (mean age at baseline, 13.9 years; 67% female; 39% White, 34% Black, 33% Hispanic). Neighborhood violence was measured as the homicide frequency in a child's Census block group in the five years before study entry. Fasting blood was drawn at study entry and two years later (in eighth and tenth grade). The blood was used to quantify protein biomarkers of systemic inflammatory activity and perform genome-wide expression profiling of isolated monocytes. Neighborhood violence was associated with higher systemic inflammatory activity at both assessments. It also was associated with a monocyte transcriptional profile indicative of increased signaling along the nuclear factor-kappa B (NF-κB) and activator protein 1 (AP-1) control pathways, which are key orchestrators of pro-inflammatory effector functions. Neighborhood violence also was associated with transcriptional indications of higher beta-adrenergic and lower glucocorticoid signaling, which could function as neuroendocrine conduits linking threatening experiences with inflammatory activity. Neighborhood violence was not associated with two-year changes in protein biomarkers, although it did presage a transcriptional profile indicative of increasing AP-1 and declining glucocorticoid signaling over follow-up. Collectively, these observations highlight cellular and molecular pathways that could underlie health risks associated with neighborhood violence., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Inflammatory pathways predict antidepressant treatment non-response among individuals with major depression; yet, this phenomenon may have broader transdiagnostic and transtherapeutic relevance. Among trauma-exposed mothers (M age  = 32 years) and their young children (M age  = 4 years), we tested whether genomic and proteomic biomarkers of pro-inflammatory imbalance prospectively predicted treatment response (PTSD and depression) to an empirically-supported behavioral treatment. Forty-three mother-child dyads without chronic disease completed Child Parent Psychotherapy (CPP) for roughly 9 months. Maternal blood was drawn pre-treatment, CD14 + monocytes isolated, gene expression derived from RNA sequencing (n = 34; Illumina HiSeq 4000;TruSeqcDNA library), and serum assayed (n = 43) for C-Reactive Protein (CRP) and interleukin-1ß (IL-1ß). Symptoms of PTSD and depression decreased significantly from pre- to post-treatment for both mothers and children (all p's < 0.01). Nonetheless, a higher pre-treatment maternal pro-inflammatory imbalance of M1-like versus M2-like macrophage-associated RNA expression (M1/M2) (ß = 0.476, p = .004) and IL-1ß (ß=0.333, p = .029), but not CRP, predicted lesser improvements in maternal PTSD symptoms, unadjusted and adjusting for maternal age, BMI, ethnicity, antidepressant use, income, education, and US birth. Only higher pre-treatment M1/M2 predicted a clinically-relevant threshold of PTSD non-response among mothers (OR = 3.364, p = .015; ROC-AUC = 0.78). Additionally, higher M1/M2 predicted lesser decline in maternal depressive symptoms (ß = 0.556, p = .001), though not independent of PTSD symptoms. For child outcomes, higher maternal IL-1ß significantly predicted poorer PTSD and depression symptom trajectories (ß's = 0.318-0.429, p's < 0.01), while M1/M2 and CRP were marginally associated with poorer PTSD symptom improvement (ß's = 0.295-0.333, p's < 0.056). Pre-treatment pro-inflammatory imbalance prospectively predicts poorer transdiagnostic symptom response to an empirically-supported behavioral treatment for trauma-exposed women and their young children., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Breast cancer is the most common cancer among women in the US, and women of low socioeconomic status (SES) show markedly poorer outcomes than those of high SES. SES may influence health through inflammation, although links between SES and inflammatory biomarkers have not been investigated in women with breast cancer. This study tested the hypothesis that breast cancer patients of lower SES would show higher levels of inflammation than those of higher SES. BMI was examined as a mediator of this association., Methods: Women recently diagnosed with early-stage breast cancer (N = 194) were recruited before neoadjuvant or adjuvant therapy. Participants completed questionnaires and provided blood samples for immune assessment. SES was indexed by participants' self-reported education and annual household income, BMI was determined by height and weight measurements, and blood was assayed for inflammatory biomarkers linked with cancer outcomes: IL-6, CRP, TNF-α, and sTNF-RII. General linear models tested associations between SES and inflammation, and mediation models examined indirect effects through BMI., Results: Consistent with hypotheses, education status was associated with CRP, (F(2,185) = 4.72, p = 0.001), and sTNF-RII, (F(2,185) = 4.19, p = 0.02), such that lower education was associated with higher levels of both biomarkers. Further, BMI mediated the associations between education and CRP, (95% CIs [-0.62, -0.11; -0.76, -0.21]), sTNF-RII, (95% CIs [-0.09, -0.01; -0.10, -0.02]), and IL-6, (95% CIs [-0.32, -0.05; -0.38, -0.09]). Annual household income was not significantly associated with inflammation (ps > 0.25), and indirect effects on inflammation through BMI were not significant., Conclusions: Lower education was associated with higher levels of inflammation in this sample, which may presage poor breast cancer-related and clinical outcomes. SES should inform the development of interventions targeting BMI and inflammation in breast cancer., (Copyright © 2021 Elsevier Inc. All rights reserved.)

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 (M age  = 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., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The vagus nerve mediates parasympathetic nervous system control of peripheral physiological processes including cardiovascular activity and immune response. In mice, tonic vagal activation down-regulates inflammation via nicotinic acetylcholine receptor-mediated inhibition of the pro-inflammatory transcription factor NF-κB in monocyte/macrophages. Because Type I interferon and pro-inflammatory genes are regulated reciprocally at the level of transcription factor activation and cell differentiation, we hypothesized that vagal activity would up-regulate Type I interferon response genes concurrently with inflammatory downregulation in human immune cells. We mapped empirical individual differences in the circulating leukocyte transcriptome and vagal activity indexed by high frequency (0.15-0.40 Hz) heart rate variability (HF-HRV) in 380 participants in the Midlife in the US study. Here we show that promoter-based bioinformatics analyses linked greater HF-HRV to reduced NF-κB activity and increased activity of IRF transcription factors involved in Type I interferon response (independent of β-antagonists, BMI, smoking, heavy alcohol consumption, and demographic factors). Transcript origin analyses implicated myeloid lineage immune cells as targets, representing per-cell alterations in gene transcription as HF-HRV was not associated with differential prevalence of leukocyte subsets. These findings support the concept of parasympathetic inhibition of pro-inflammatory gene expression in humans and up-regulation of Type I interferons that could augment host defense against viral infections., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Stress 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., Methods: Women 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., Results: Stress 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 < .001) among women who reported high cancer-related stress. Results were independent of age, BMI, race and cancer-related covariates., Conclusions: Stress was found to heighten sensitivity to inflammation-associated depressive symptoms over a 2-year period, with notably stronger effects for subjective stress responses to a concurrent life event. Individuals who are most distressed following a major life event may exhibit the greatest risk for inflammation-induced depression., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Childhood 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., Methods: Women (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., Results: Based 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., Conclusions: In 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., (Copyright © 2020. Published by Elsevier Inc.)

Background: Rates 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 (M age  = 18.37, SD = 0.51)., Method: Participants (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., Results: Adolescents 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 < 16). Bioinformatics analyses suggested that this pattern of differential gene expression was mediated by greater activity of the pro-inflammatory transcription factor, nuclear factor-kappa B (NF-κB), and reduced activity of glucocorticoid receptors (GRs) and interferon response factors (IRFs). Additional analyses implicated monocytes, B cells, and dendritic cells as primary cellular sources of the observed gene expression patterns associated with depressive symptoms., Conclusion: Results are consistent with past work demonstrating links between depression and altered immunity. They provide a molecular basis for these associations and suggest that the underlying molecular signature may emerge as early as late adolescence when rates of depression tend to increase., (Copyright © 2019 Elsevier Inc. All rights reserved.)

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., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Recent research in functional genomics shows that social stressors affect the expression of immune response genes. These effects are mediated in part via our adaptive capacity for intracellular molecules to respond to extracellular signals, a process called signal transduction. Under this framework, one-way stressors can be transduced into cellular changes is through central nervous system (CNS) modulation of peripheral neural, endocrine, and molecular activity. Mindfulness meditation is a consciousness discipline used to cultivate attention and self-regulation, and may thus be relevant to the signal transduction process outlined in the social genomics literature. In this opinion article, we briefly review results from existing controlled trials that test the effects of mindfulness meditation on gene expression. We then speculate on a mind-body conceptual model, grounded in existing social genomics theory. In the spirit of hypothesis generation, we argue that mindfulness meditation changes brain activity patterns related to attention, self-regulation, and threat evaluation and so may alter the signal transduction process that regulates the expression of immune response genes., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Stress 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., Methods: A 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., Results: Women 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., Conclusions: Prenatal 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., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Previous studies have linked plasma inflammatory markers to elevated fatigue in patients with head and neck cancer (HNC). To identify the molecular mechanisms underlying this association, we conducted promoter-based bioinformatics analyses to determine the relationship between fatigue and specific gene expression profiles associated with inflammation in human papillomavirus (HPV)-related and -unrelated HNC patients undergoing treatment. Patients with newly diagnosed HNC without distant metastasis were assessed at baseline (pre-radiotherapy) and one-month post-radiotherapy. Fatigue was measured by the Multidimensional Fatigue Inventory. Genome-wide gene expression profiles were collected from peripheral blood mononuclear cells (PBMC). Promoter-based bioinformatics analyses were employed to identify transcription control pathways underlying transcriptomic correlates of fatigue in the sample as a whole and in HPV-related and HPV-unrelated HNC patients separately. In transcriptome profiling analyses of PBMC from 44 patients, TELiS bioinformatics analyses linked fatigue to increased nuclear factor-kappa B (NF-kB) transcriptional activity and decreased interferon regulatory factor family (IRF) transcription factor activity. Patients with HPV-related HNC showed lower levels of fatigue-related gene expression profile compared to HPV-unrelated HNC. Fatigue in HNC patients undergoing treatment is associated with gene expression profiles consistent with the conserved transcriptional response to adversity (CTRA) characterized by increased proinflammatory and decreased anti-antiviral transcriptional activity. Interestingly, this CTRA response was mitigated in patients with HPV-related HNC and may explain the lower level of fatigue they experience relative to HPV-unrelated HNC., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Catecholamines and prostaglandins are secreted abundantly during the perioperative period in response to stress and surgery, and were shown by translational studies to promote tumor metastasis. Here, in a phase-II biomarker clinical trial in breast cancer patients (n = 38), we tested the combined perioperative use of the β-blocker, propranolol, and the COX2-inhibitor, etodolac, scheduled for 11 consecutive perioperative days, starting 5 days before surgery. Blood samples were taken before treatment (T1), on the mornings before and after surgery (T2&T3), and after treatment cessation (T4). Drugs were well tolerated. Results based on a-priori hypotheses indicated that already before surgery (T2), serum levels of pro-inflammatory IL-6, CRP, and IFNγ, and anti-inflammatory, cortisol and IL-10, increased. At T2 and/or T3, drug treatment reduced serum levels of the above pro-inflammatory cytokines and of TRAIL, as well as activity of multiple inflammation-related transcription factors (including NFκB, STAT3, ISRE), but not serum levels of cortisol, IL-10, IL-18, IL-8, VEGF and TNFα. In the excised tumor, treatment reduced the expression of the proliferation marker Ki-67, and positively affected its transcription factors SP1 and AhR. Exploratory analyses of transcriptome modulation in PBMCs revealed treatment-induced improvement at T2/T3 in several transcription factors that in primary tumors indicate poor prognosis (CUX1, THRa, EVI1, RORa, PBX1, and T3R), angiogenesis (YY1), EMT (GATA1 and deltaEF1/ZEB1), proliferation (GATA2), and glucocorticoids response (GRE), while increasing the activity of the oncogenes c-MYB and N-MYC. Overall, the drug treatment may benefit breast cancer patients through reducing systemic inflammation and pro-metastatic/pro-growth biomarkers in the excised tumor and PBMCs., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Almost 2.8 million men in the U.S. are living with prostate cancer (PC), accounting for 40% of all male cancer survivors. Men diagnosed with prostate cancer may experience chronic and debilitating treatment side effects, including sexual and urinary dysfunction, pain and fatigue. Side effects can be stressful and can also lead to poor psychosocial functioning. Prior trials reveal that group-based cognitive behavioral stress and self-management (CBSM) is effective in reducing stress and mitigating some of these symptoms, yet little is known about the effects of culturally-translated CBSM among Spanish-speaking men with PC. This manuscript describes the rationale and study design of a multi-site, randomized controlled trial to determine whether participation in a culturally adapted cognitive behavioral stress management (C-CBSM) intervention leads to significantly greater reductions in symptom burden and improvements in health-related quality of life relative to participation in a non-culturally adapted cognitive behavioral stress management (CBSM) intervention. Participants (N = 260) will be Spanish-speaking Hispanic/Latino men randomized to the standard, non-culturally adapted CBSM intervention (e.g., cognitive behavioral strategies, stress management, and health maintenance) or the culturally adapted C-CBSM intervention (e.g., content adapted to be compatible with Hispanic/Latino cultural patterns and belief systems, meanings, values and social context) for 10 weeks. Primary outcomes (i.e., disease-specific symptom burden and health-related quality of life) will be assessed across time. We hypothesize that a culturally adapted C-CBSM intervention will be more efficacious in reducing symptom burden and improving health-related quality of life among Hispanic/Latino men when compared to a non-culturally adapted CBSM intervention., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Children from economically disadvantaged families experience worse cognitive, psychiatric, and medical outcomes compared to more affluent youth. Preclinical models suggest some of the adverse influence of disadvantage could be transmitted during gestation via maternal immune activation, but this hypothesis has not been tested in humans. It also remains unclear whether prenatal interventions can mitigate such effects. To fill these gaps, we conducted two studies. Study 1 characterized the socioeconomic conditions of 79 women during pregnancy. At delivery, placenta biopsies and umbilical blood were collected for transcriptional profiling. Maternal disadvantage was associated with a transcriptional profile indicative of higher immune activation and slower fetal maturation, particularly in pathways related to brain, heart, and immune development. Cord blood cells of disadvantaged newborns also showed indications of immaturity, as reflected in down-regulation of pathways that coordinate myeloid cell development. These associations were independent of fetal sex, and characteristics of mothers (age, race, adiposity, diabetes, pre-eclampsia) and babies (delivery method, gestational age). Study 2 performed the same transcriptional analyses in specimens from 20 women participating in CenteringPregnancy, a group-based psychosocial intervention, and 20 women in traditional prenatal care. In both placenta biopsies and cord blood, women in CenteringPregnancy showed up-regulation of transcripts found in Study 1 to be most down-regulated in conjunction with disadvantage. Collectively, these results suggest socioeconomic disparities in placental biology are evident at birth, and provide clues about the mechanistic origins of health disparities. They also suggest the possibility that psychosocial interventions could have mitigating influences., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose: A growing number of cancer survivors suffer high levels of distress, depression and stress, as well as sleep disturbance, pain and fatigue. Two different mind-body interventions helpful for treating these problems are Mindfulness-Based Cancer Recovery (MBCR) and Tai Chi/Qigong (TCQ). However, while both interventions show efficacy compared to usual care, they have never been evaluated in the same study or directly compared. This study will be the first to incorporate innovative design features including patient choice while evaluating two interventions to treat distressed cancer survivors. It will also allow for secondary analyses of which program best targets specific symptoms in particular groups of survivors, based on preferences and baseline characteristics., Methods and Significance: The design is a preference-based multi-site randomized comparative effectiveness trial. Participants (N=600) with a preference for either MBCR or TCQ will receive their preferred intervention; while those without a preference will be randomized into either intervention. Further, within the preference and non-preference groups, participants will be randomized into immediate intervention or wait-list control. Total mood disturbance on the Profile of mood states (POMS) post-intervention is the primary outcome. Other measures taken pre- and post-intervention and at 6-month follow-up include quality of life, psychological functioning, cancer-related symptoms and physical functioning. Exploratory analyses investigate biomarkers (cortisol, cytokines, blood pressure/Heart Rate Variability, telomere length, gene expression), which may uncover potentially important effects on key biological regulatory and antineoplastic functions. Health economic measures will determine potential savings to the health system., (Copyright © 2017 Elsevier Inc. All rights reserved.)

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., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Sleep disturbance is associated with activation of systemic and cellular inflammation, as well as proinflammatory transcriptional profiles in circulating leukocytes. Whether treatments that target insomnia-related complaints might reverse these markers of inflammation in older adults with insomnia is not known., Methods: In this randomized trial, 123 older adults with insomnia were randomly assigned to cognitive-behavioral therapy for insomnia (CBT-I), tai chi chih (TCC), or sleep seminar education active control condition for 2-hour sessions weekly over 4 months with follow-up at 7 and 16 months. We measured C-reactive protein (CRP) at baseline and months 4 and 16; toll-like receptor-4 activated monocyte production of proinflammatory cytokines at baseline and months 2, 4, 7, and 16; and genome-wide transcriptional profiling at baseline and month 4., Results: As compared with sleep seminar education active control condition, CBT-I reduced levels of CRP (months 4 and 16, ps < .05), monocyte production of proinflammatory cytokines (month 2 only, p < .05), and proinflammatory gene expression (month 4, p < .01). TCC marginally reduced CRP (month 4, p = .06) and significantly reduced monocyte production of proinflammatory cytokines (months 2, 4, 7, and 16; all ps < .05) and proinflammatory gene expression (month 4, p < .001). In CBT-I and TCC, TELiS promoter-based bioinformatics analyses indicated reduced activity of nuclear factor-κB and AP-1., Conclusions: Among older adults with insomnia, CBT-I reduced systemic inflammation, TCC reduced cellular inflammatory responses, and both treatments reduced expression of genes encoding proinflammatory mediators. The findings provide an evidence-based molecular framework to understand the potential salutary effects of insomnia treatment on inflammation, with implications for inflammatory disease risk., (Copyright © 2015 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Chronic stress is associated with morbidity and mortality from numerous conditions, many of whose pathogenesis involves persistent inflammation. Here, we examine how chronic stress influences signaling pathways that regulate inflammation in monocytes. The sample consisted of 33 adults caring for a family member with glioblastoma and 47 controls whose lives were free of major stressors. The subjects were assessed four times over eight months. Relative to controls, caregivers' monocytes showed increased expression of genes bearing response elements for nuclear-factor kappa B, a key pro-inflammatory transcription factor. Simultaneously, caregivers showed reduced expression of genes with response elements for the glucocorticoid receptor, a transcription factor that conveys cortisol's anti-inflammatory signals to monocytes. Transcript origin analyses revealed that CD14+/CD16- cells, a population of immature monocytes, were the predominate source of inflammatory gene expression among caregivers. We considered hormonal, molecular, and functional explanations for caregivers' decreased glucocorticoid-mediated transcription. Across twelve days, the groups displayed similar diurnal cortisol profiles, suggesting that differential adrenocortical activity was not involved. Moreover, the groups' monocytes expressed similar amounts of glucocorticoid receptor protein, suggesting that differential receptor availability was not involved. In ex vivo studies, subjects' monocytes were stimulated with lipopolysaccharide, and caregivers showed greater production of the inflammatory cytokine interleukin-6 relative to controls. However, no group differences in functional glucocorticoid sensitivity were apparent; hydrocortisone was equally effective at inhibiting cytokine production in caregivers and controls. These findings may help shed light on the mechanisms through which caregiving increases vulnerability to inflammation-related diseases., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Chronic sympathetic nervous system activation results in increased angiogenesis and tumor growth in orthotopic mouse models of ovarian carcinoma. However, the mechanistic effects of such activation on the tumor vasculature are not well understood. Dopamine (DA), an inhibitory catecholamine, regulates the functions of normal and abnormal blood vessels. Here, we examined whether DA, an inhibitory catecholamine, could block the effects of chronic stress on tumor vasculature and tumor growth. Exogenous administration of DA not only decreased tumor microvessel density but also increased pericyte coverage of tumor vessels following daily restraint stress in mice. Daily restraint stress resulted in significantly increased tumor growth in the SKOV3ip1 and HeyA8 ovarian cancer models. DA treatment blocked stress-mediated increases in tumor growth and increased pericyte coverage of tumor endothelial cells. Whereas the antiangiogenic effect of DA is mediated by dopamine receptor 2 (DR2), our data indicate that DA, through DR1, stimulates vessel stabilization by increasing pericyte recruitment to tumor endothelial cells. DA significantly stimulated migration of mouse 10T1/2 pericyte-like cells in vitro and increased cyclic adenosine mono-phosphate (cAMP) levels in these cells. Moreover, DA or the DR1 agonist SKF 82958 increased platinum concentration in SKOV3ip1 tumor xenografts following cisplatin administration. In conclusion, DA stabilizes tumor blood vessels through activation of pericyte cAMP-protein kinase A signaling pathway by DR1. These findings could have implications for blocking the stimulatory effects of chronic stress on tumor growth.

During the past decade, new studies have continued to shed light on the role of neuroendocrine regulation of downstream physiological and biological pathways relevant to cancer growth and progression. More specifically, our knowledge of the effects of the sympathetic nervous system (SNS) on cancer biology has been greatly expanded by new data demonstrating how the cellular immune response, inflammatory processes, tumor-associated angiogenesis, and tumor cell invasion and survival converge to promote tumor growth. This review will summarize these studies, while synthesizing clinical, cellular and molecular research that has continued to unearth the biological events mediating the interplay between SNS-related processes and cancer progression., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: There is mounting interest in the hypothesis that inflammation contributes to the pathogenesis of depression and underlies depressed patients' vulnerability to comorbid medical conditions. However, research on depression and inflammation has yielded conflicting findings, fostering speculation that these conditions associate only in certain subgroups, such as patients exposed to childhood adversity., Methods: We studied 147 female adolescents. All were in good health at baseline but at high risk for depression because of family history or cognitive vulnerability. Subjects were assessed every 6 months for 2.5 years, undergoing diagnostic interviews and venipuncture for measurement of two inflammatory biomarkers, C-reactive protein (CRP) and interleukin-6 (IL-6). Childhood adversity was indexed by parental separation, low socioeconomic status, and familial psychopathology., Results: Multilevel models indicated that childhood adversity promotes clustering of depression and inflammation. Among subjects exposed to high childhood adversity, the transition to depression was accompanied by increases in both CRP and IL-6. Higher CRP remained evident 6 months later, even after depressive symptoms had abated. These lingering effects were bidirectional, such that among subjects with childhood adversity, high IL-6 forecasted depression 6 months later, even after concurrent inflammation was considered. This coupling of depression and inflammation was not apparent in subjects without childhood adversity., Conclusions: These findings suggest that childhood adversity promotes the formation of a neuroimmune pipeline in which inflammatory signaling between the brain and periphery is amplified. Once established, this pipeline leads to a coupling of depression and inflammation, which may contribute to later affective difficulties and biomedical complications., (Copyright © 2012 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Clinical studies suggest that stress-related biobehavioral factors can accelerate the progression of hematopoietic cancers such as acute lymphoblastic leukemia (ALL), but it is unclear whether such effects are causal or what biological pathways mediate such effects. Given the network of sympathetic nervous system (SNS) fibers that innervates the bone marrow to regulate normal (non-leukemic) hematopoietic progenitor cells, we tested the possibility that stress-induced SNS signaling might also affect ALL progression. In an orthotopic mouse model, Nalm-6 human pre-B ALL cells were transduced with the luciferase gene for longitudinal bioluminescent imaging and injected i.v. into male SCID mice for bone marrow engraftment. Two weeks of daily restraint stress significantly enhanced ALL tumor burden and dissemination in comparison to controls, and this effect was blocked by the β-adrenergic antagonist, propranolol. Although Nalm-6 ALL cells expressed mRNA for β1- and β3-adrenergic receptors, they showed no evidence of cAMP signaling in response to norepinephrine, and norepinephrine failed to enhance Nalm-6 proliferation in vitro. These results show that chronic stress can accelerate the progression of human pre-B ALL tumor load via a β-adrenergic signaling pathway that likely involves indirect regulation of ALL biology via alterations in the function of other host cell types such as immune cells or the bone marrow microenvironment., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Noradrenergic pathways have been implicated in growth and progression of ovarian cancer. Intratumoral norepinephrine (NE) has been shown to increase with stress in an animal cancer model, but little is known regarding how tumor NE varies with disease stage and with biobehavioral factors in ovarian cancer patients. This study examined relationships between pre-surgical measures of social support, depressed mood, perceived stress, anxiety, tumor histology and tumor catecholamine (NE and epinephrine [E]) levels among 68 ovarian cancer patients. We also examined whether associations observed between biobehavioral measures and tumor catecholamines extended to other compartments. Higher NE levels were found in advanced stage (p=0.006) and higher grade (p=0.001) tumors. Adjusting for stage, grade, and peri-surgical beta blockers, patients with a perceived lack of social support had significantly higher tumor NE (β=-0.29, p=0.012). A similar trend was seen for social support and ascites NE (adjusting for stage, peri-surgical beta blockers and caffeine: β=-0.50, p=0.075), but not for plasma NE. Other biobehavioral factors were not related to tumor, ascites, or plasma NE (p values >0.21). Tumor E was undetectable in the majority of tumors and thus E was not further analyzed. In summary, these results suggest that tumor NE provides distinct information from circulating plasma concentrations. Tumor NE levels were elevated in relationship to tumor grade and stage. Low subjective social support was associated with elevated intratumoral NE. As beta-adrenergic signaling is related to key biological pathways involved in tumor growth, these findings may have implications for patient outcomes in ovarian cancer., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Fatigue is highly prevalent in the general population and is one of the most common side effects of cancer treatment. There is growing evidence that pro-inflammatory cytokines play a role in cancer-related fatigue, although the molecular mechanisms for chronic inflammation and fatigue have not been determined. The current study utilized genome-wide expression microarrays to identify differences in gene expression and associated alterations in transcriptional activity in leukocytes from breast cancer survivors with persistent fatigue (n=11) and non-fatigued controls (n=10). We focused on transcription of inflammation-related genes, particularly those responsive to the pro-inflammatory NF-κB transcription control pathway. Further, given the role of glucocorticoids as key regulators of inflammatory processes, we examined transcription of glucocorticoid-responsive genes indicative of potential glucocorticoid receptor (GR) desensitization. Plasma levels of cortisol were also assessed. Consistent with hypotheses, results showed increased expression of transcripts with response elements for NF-κB, and reduced expression of transcripts with response elements for glucocorticoids (p<.05) in fatigued breast cancer survivors. No differences in plasma levels of cortisol were observed. These data indicate that increased activity of pro-inflammatory transcription factors may contribute to persistent cancer-related fatigue and provide insight into potential mechanisms for tonic increases in NF-κB activity, specifically decreased expression of GR anti-inflammatory transcription factors., (Copyright © 2010 Elsevier Inc. All rights reserved.)

There is growing evidence that temperament/personality factors are associated with immune function and health-related outcomes. Neuroticism, in particular, is a risk-factor for several diseases, many with a strong inflammatory component. We propose that neuroticism (or nervous temperament in monkeys) is related to dysregulation of immune function by glucocorticoids. The present study tested the hypothesis that animals with a nervous temperament would show no relationship between cortisol concentrations and leukocyte numbers in peripheral blood (an easily obtainable measure of glucocorticoid-mediated immune function), while animals low on this factor would show expected relationships. Infant rhesus monkeys (n=1507) experienced a standardized testing procedure involving blood sampling, behavioral tests, and temperament ratings. Results confirmed the hypothesis: low-nervous animals showed the expected positive relationship between cortisol levels and neutrophil numbers, while high-nervous animals showed no relationship. High-nervous animals also showed elevated cortisol concentrations at most sample points, and responded to a human challenge with more negative emotional behavior. These data suggest that individuals with a nervous temperament show evidence of glucocorticoid desensitization of immune cells. Differences with other studies, including the specific types of leukocytes that are affected, are discussed, and implications for disease processes are suggested., (Copyright © 2010 Elsevier Inc. All rights reserved.)

To assess the biological impact of time spent helping the family during the teenage years, we examined circulating levels of interleukin-6 (IL-6), soluble interleukin-6 receptor (sIL-6r), and C-reactive protein (CRP) in 64 adolescents (M(age)=17.79 years) from Latin American and European backgrounds. Analyses of nightly diary checklists over 14 days showed that the amount of time spent helping the family in a variety of ways, such as cooking, cleaning, and sibling care, was associated with long-term elevations of sIL-6r and CRP, even after controlling for ethnicity, parental education, BMI, substance use, distress, and frequency of daily family assistance 2 years earlier. However, adolescents who derived a greater sense of role fulfillment from helping the family on a daily basis had lower levels of sIL-6r and CRP as compared to their peers who engaged in the same amount of family assistance. Additional work should explore the family context that drives high levels of assistance among adolescents, as well as the variety of ways adolescents may derive meaning from this activity.

Motivated by previous indications that beta-adrenergic signaling can regulate tumor cell gene expression in model systems, we sought to determine whether similar dynamics occur in primary human ovarian cancer. DNA microarray analyses of 10 ovarian carcinomas identified 266 human transcripts that were differentially expressed in tumors from patients with elevated biobehavioral risk factors (high depressive symptoms and low social support) relative to grade- and stage-matched tumors from low-risk patients. Promoter-based bioinformatic analyses indicated increased activity of several beta-adrenergically-linked transcription control pathways, including CREB/ATF, NF-kappaB/Rel, STAT, and Ets family transcription factors. Consistent with increased beta-adrenergic signaling, high biobehavioral risk patients also showed increased intra-tumor concentrations of norepinephrine (but no difference in plasma norepinephrine). These data show that genome-wide transcriptional profiles are significantly altered in tumors from patients with high behavioral risk profiles, and they identify beta-adrenergic signal transduction as a likely mediator of those effects.

Clinical and animal studies now support the notion that psychological factors such as stress, chronic depression, and lack of social support might promote tumor growth and progression. Recently, cellular and molecular studies have started to identify biological processes that could mediate such effects. This review provides a mechanistic understanding of the relationship between biological and behavioral influences in cancer and points to more comprehensive behavioral and pharmacological approaches for better patient outcomes.

Converging evidence from basic and clinical studies suggests a role for proinflammatory cytokines in cancer-related fatigue, although the etiology of elevated inflammatory processes is unclear. We examined single nucleotide polymorphisms (SNPs) in the promoters of cytokine genes as genetic risk factors for cytokine-related fatigue in 33 fatigued and 14 non-fatigued breast cancer survivors, focusing on promoter sequence polymorphisms in IL1B and IL6 associated with differential expression of proinflammatory cytokines. Predictors of fatigue included presence of at least one cytosine at IL1B -511 (95%CI=0.91-16.6, p=.007) and homozygosity for either variant of the IL6 -174 genotype (G/G or C/C; 95%CI=1.12-17.9, p=.027). Associations between fatigue status and IL1B genotype remained significant after covariate adjustment for demographic, biobehavioral and treatment-related factors. These findings provide preliminary evidence that polymorphisms in IL1B may serve as a potential risk factor for persistent fatigue in the aftermath of cancer.

Recent small-scale genomics analyses suggest that physiologic regulation of pro-inflammatory gene expression by endogenous glucocorticoids may be compromised in individuals who experience chronic social isolation. The present study assessed the relationship between leukocyte distributional sensitivity to glucocorticoid regulation and subjective social isolation in a large population-based sample of older adults. Initial analyses confirmed that circulating neutrophil percentages were elevated, and circulating lymphocyte and monocyte percentages were suppressed, in direct proportion to circulating cortisol levels. However, leukocyte distributional sensitivity to endogenous glucocorticoids was abrogated in individuals reporting either occasional or frequent experiences of subjective social isolation. This finding held in both non-parametric univariate analyses and in multivariate linear models controlling for a variety of biological, social, behavioral, and psychological confounders. The present results suggest that social factors may alter immune cell sensitivity to physiologic regulation by the hypothalamic-pituitary-adrenal axis in ways that could ultimately contribute to the increased physical health risks associated with social isolation.

Background: Accumulating evidence suggests that sleep disturbance is associated with inflammation and related disorders including cardiovascular disease, arthritis, and diabetes mellitus. This study was undertaken to test the effects of sleep loss on activation of nuclear factor (NF)-kappaB, a transcription factor that serves a critical role in the inflammatory signaling cascade., Methods: In 14 healthy adults (seven women; seven men), peripheral blood mononuclear cell NF-kappaB was repeatedly assessed, along with enumeration of lymphocyte subpopulations, in the morning after baseline sleep, partial sleep deprivation (awake from 11 pm to 3:00 am), and recovery sleep., Results: In the morning after a night of sleep loss, mononuclear cell NF-kappaB activation was significantly greater compared with morning levels following uninterrupted baseline or recovery sleep, in which the response was found in female but not in male subjects., Conclusions: These results identify NF-kappaB activation as a molecular pathway by which sleep disturbance may influence leukocyte inflammatory gene expression and the risk of inflammation-related disease.