Natural selection of immune and metabolic genes associated with health in two lowland Bolivian populations.

A growing body of work has addressed human adaptations to diverse environments using genomic data, but few studies have connected putatively selected alleles to phenotypes, much less among underrepresented populations such as Amerindians. Studies of natural selection and genotype-phenotype relationships in underrepresented populations hold potential to uncover previously undescribed loci underlying evolutionarily and biomedically relevant traits. Here, we worked with the Tsimane and the Moseten, two Amerindian populations inhabiting the Bolivian lowlands. We focused most intensively on the Tsimane, because long-term anthropological work with this group has shown that they have a high burden of both macro and microparasites, as well as minimal cardiometabolic disease or dementia. We therefore generated genome-wide genotype data for Tsimane individuals to study natural selection, and paired this with blood mRNA-seq as well as cardiometabolic and immune biomarker data generated from a larger sample that included both populations. In the Tsimane, we identified 21 regions that are candidates for selective sweeps, as well as 5 immune traits that show evidence for polygenic selection (e.g., C-reactive protein levels and the response to coronaviruses). Genes overlapping candidate regions were strongly enriched for known involvement in immune-related traits, such as abundance of lymphocytes and eosinophils. Importantly, we were also able to draw on extensive phenotype information for the Tsimane and Moseten and link five regions (containing PSD4, MUC21 and MUC22, TOX2, ANXA6, and ABCA1) with biomarkers of immune and metabolic function. Together, our work highlights the utility of pairing evolutionary analyses with anthropological and biomedical data to gain insight into the genetic basis of health-related traits.

Social stressors associated with age-related T lymphocyte percentages in older US adults: Evidence from the US Health and Retirement Study.

Exposure to stress is a risk factor for poor health and accelerated aging. Immune aging, including declines in naïve and increases in terminally differentiated T cells, plays a role in immune health and tissue specific aging, and may contribute to elevated risk for poor health among those who experience high psychosocial stress. Past data have been limited in estimating the contribution of life stress to the development of accelerated immune aging and investigating mediators such as lifestyle and cytomegalovirus (CMV) infection. This study utilizes a national sample of 5,744 US adults over age 50 to assess the relationship of social stress (viz., everyday discrimination, stressful life events, lifetime discrimination, life trauma, and chronic stress) with flow cytometric estimates of immune aging, including naïve and terminally differentiated T cell percentages and the ratio of CD4+ to CD8+ cells. Experiencing life trauma and chronic stress was related to a lower percentage of CD4+ naïve cells. Discrimination and chronic stress were each associated with a greater percentage of terminally differentiated CD4+ cells. Stressful life events, high lifetime discrimination, and life trauma were related to a lower percentage of CD8+ naïve cells. Stressful life events, high lifetime discrimination, and chronic stress were associated with a higher percentage of terminally differentiated CD8+ cells. High lifetime discrimination and chronic stress were related to a lower CD4+:CD8+ ratio. Lifestyle factors and CMV seropositivity partially reduced these effects. Results identify psychosocial stress as a contributor to accelerating immune aging by decreasing naïve and increasing terminally differentiated T cells.

ZIP Code to Genomic Code: Neighborhood Disadvantage, Aggressive Breast Cancer Biology, and Breast Cancer Outcomes.

OBJECTIVE: To determine the association between objective (geospatial) and subjective (perceived) measures of neighborhood disadvantage (ND) and aggressive breast cancer tumor biology, defined using validated social adversity-associated transcription factor (TF) activity and clinical outcomes. BACKGROUND: ND is associated with shorter breast cancer recurrence-free survival (RFS), independent of individual, tumor, and treatment characteristics, suggesting potential unaccounted biological mechanisms by which ND influences RFS. METHODS: We quantified TF-binding motif prevalence within promoters of differentially expressed genes for 147 tissue samples prospectively collected on the protocol. Covariate-adjusted multivariable regression analyzed objective and subjective ND scores with 5 validated TFs of social adversity and aggressive biology-pro-inflammatory activity [nuclear factor-κB ( NF-kB ), activator protein 1 ( AP-1 )], sympathetic nervous system (SNS) activity [cyclic 3'-5' adenosine monophosphate response element-binding protein ( CREB )], and protective cellular responses [interferon-regulatory factor ( IRF ) and signal transducer and activator of transcription ( STAT )]. To clinically validate these TFs as prognostic biomarkers of aggressive biology, logistic regression and multivariable Cox proportional-hazards models analyzed their association with Oncotype DX scores and RFS, respectively. RESULTS: Increasing objective ND was associated with aggressive tumor biology (up-regulated NF-kB , activator protein 1, down-regulated IRF , and signal transducer and activator of transcription) and SNS activation (up-regulated CREB ). Increasing subjective ND (eg, threat to safety) was associated with up-regulated NF-kB and CREB and down-regulated IRF . These TF patterns were associated with high-risk Oncotype DX scores and shorter RFS. CONCLUSIONS: In the largest human social genomics study, objective and subjective ND were significantly associated with TFs of aggressive biology and SNS activation. These TFs also correlated with worse clinical outcomes, implicating SNS activation as one potential mechanism behind ND survival disparities. These findings remain to be validated in a national cohort.

A tale of two marital stressors: Comparing proinflammatory responses to partner distress and marital conflict.

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.

Psychoneuroimmunology in multiple myeloma and autologous hematopoietic stem cell transplant: Opportunities for research among patients and caregivers.

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.

Type I interferons, inflammation, and fatigue in a longitudinal RNA study of women with breast cancer.

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.

Peri-operative individually tailored psychological intervention in breast cancer patients improves psychological indices and molecular biomarkers of metastasis in excised tumors.

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.

Perioperative escape from dormancy of spontaneous micro-metastases: A role for malignant secretion of IL-6, IL-8, and VEGF, through adrenergic and prostaglandin signaling.

We recently showed that a minimally-invasive removal of MDA-MB-231HM 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-231HM 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 ß-adrenergic and COX-2 inhibition, using propranolol + etodolac, maintained metastatic dormancy following laparotomy. In-vitro, ß-adrenergic agonists (epinephrine or metaproterenol) and prostaglandin-E2 markedly increased MDA-MB-231HM 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.

The role of early life adversity and inflammation in stress-induced change in reward and risk processes among adolescents.

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.

Social relationships and epigenetic aging in older adulthood: Results from the Health and Retirement Study.

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.

Maternal early life stress is associated with pro-inflammatory processes during pregnancy.

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.

The Relationship Between Family Socioeconomic Status and Adolescent Sleep and Diurnal Cortisol.

OBJECTIVE: This study aimed to investigate the associations between indices of family socioeconomic status and sleep during adolescence and to examine whether measures of hypothalamic-pituitary-adrenal (HPA) axis functioning mediate the observed associations. METHODS: A total of 350 ethnically diverse adolescents (57% female; mean [standard deviation] age wave 1 = 16.4 [0.7] years) completed a three-wave longitudinal study in which sleep and cortisol data were collected at 2-year time intervals. Sleep duration, latency, and variability were assessed via actigraphy during a period of 8 days per study wave. Salivary cortisol was collected across 3 days per study wave to assess cortisol diurnal slope, area under the curve, and the cortisol awakening response. Adolescents' caregivers reported their education levels, family income, and economic hardship. RESULTS: A greater family income-to-needs ratio was associated with longer adolescent sleep duration ( b = 2.90, p = .023), whereas greater parental education was associated with shorter sleep duration ( b = -3.70, p = .030), less sleep latency ( b = -0.74, p = .016), and less variability across days ( b = -2.06, p = .010). Diurnal cortisol slope statistically mediated the association of parental education with sleep duration ( b = -0.48, 95% confidence interval = -1.099 to -0.042), but not the association of income-to-needs ratio with sleep duration. CONCLUSIONS: Findings suggest that parental education and family resources may have unique impacts upon sleep and HPA axis functioning during the period of adolescence. Future research is needed to examine family and behavioral factors that may underlie socioeconomic status associations with adolescent sleep and HPA axis functioning.

Psychosocial Resilience to Inflammation-Associated Depression: A Prospective Study of Breast-Cancer Survivors.

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.

Smartphone mindfulness meditation training reduces Pro-inflammatory gene expression in stressed adults: A randomized controlled trial.

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.

Prospective associations between neighborhood violence and monocyte pro-inflammatory transcriptional activity in children.

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.

Socioeconomic Status and Inflammation in Women with Early-stage Breast Cancer: Mediation by Body Mass Index.

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.

Do all patients with cancer experience fatigue? A longitudinal study of fatigue trajectories in women with breast cancer.

BACKGROUND: Fatigue 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. METHODS: Women 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. RESULTS: Five 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. CONCLUSIONS: There 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.

Only the Lonely: Expression of Proinflammatory Genes Through Family Cancer Caregiving Experiences.

OBJECTIVE: The experience of cancer elicits not only turmoil but also resilience in the family, which has been related to psychological adjustment and physical health of family caregivers. The biological pathways linking family cancer caregiving to health, however, remain poorly understood. This study examined the extent to which psychological risk and resilience factors related to a proinflammatory gene expression profile (conserved transcriptional response to adversity, or CTRA) among caregivers during the first-year postdiagnosis of a patient with colorectal cancer. METHODS: A total of 41 caregivers (mean age = 54 years, 74% female, 40% Hispanic) provided psychological data and peripheral blood samples around 4 and 12 months after diagnosis. Mixed regression models controlling for demographic and biometric factors were used to test the associations of caregiver CTRA gene expression with caregiving stress, loneliness, and lack of social support (risk factors), as well as benefit finding and meaning (resilience factors). RESULTS: When individually tested, all but benefit finding were significantly related to CTRA (R2 ≥ 0.112, p < .045). When adjusted for other factors in either the risk or resilience group, loneliness, social support, and meaning effects remained significant (R2 ≥ 0.120, p < .041). When all study factors were simultaneously adjusted (R2 = 0.139), only loneliness remained significant (p = .034). CONCLUSIONS: Findings suggest that caregiving-related transcriptional effects seem to be most pronounced when caregivers experience low social support and loneliness, as well as little meaning or purpose in their caregiving. These findings suggest that the development of new intervention strategies that prioritize reductions in caregiver loneliness may favorably impact biological mechanisms related to caregiver health.

Positive Psychosocial Factors and Oxytocin in the Ovarian Tumor Microenvironment.

OBJECTIVE: Clinical ovarian cancer research shows relationships between psychosocial factors and disease-promoting aspects of the stress response (e.g., norepinephrine and cortisol). However, little is known about how psychosocial factors might relate to beneficial hormones in the ovarian tumor microenvironment. Here we examine relationships between psychosocial factors and tumor-associated oxytocin, a hormone linked to survival and antitumor processes in ovarian cancer. METHODS: Patients with ovarian cancer (n = 96) completed assessments of positive psychosocial factors (social support, positive affect, and purpose in life) and distress (perceived stress and depression) at the time of surgery. Levels of oxytocin and interleukin (IL) 6 in ascites fluid were obtained during surgery and analyzed by enzyme-linked immunosorbent assay. Multiple regression analyses adjusting a priori for patient age and disease stage examined associations between psychosocial factors and ascites oxytocin. IL-6 was used as a covariate in secondary analyses to examine the potentially confounding effects of inflammation in these relationships. RESULTS: Higher levels of positive affect (ß = 0.22, p = .034), purpose in life (ß = 0.31, p = .021), and social nurturance (ß = 0.24, p = .024) were all related to higher levels of tumor-associated oxytocin at the time of surgery. In contrast, we found no effects for distress or social attachment. Relationships between oxytocin, purpose in life, and social nurturance were independent of IL-6, whereas positive affect was no longer significant with IL-6 in the model. CONCLUSIONS: Tumor-associated oxytocin may be a previously uninvestigated link in the relationship between psychosocial factors and health in ovarian cancer. Future studies should examine causal mechanisms of relationships observed in this study.

Parasympathetic neural activity and the reciprocal regulation of innate antiviral and inflammatory genes in the human immune system.

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 ß-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.