RESUMEN
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.
RESUMEN
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.
Asunto(s)
Conflicto Familiar , Inflamación , Matrimonio , Esposos , Estrés Psicológico , Humanos , Femenino , Masculino , Persona de Mediana Edad , Conflicto Familiar/psicología , Adulto , Anciano , Esposos/psicología , Estrés Psicológico/psicología , Estrés Psicológico/inmunología , Matrimonio/psicología , Inflamación/inmunología , Inflamación/psicología , Anciano de 80 o más Años , Satisfacción Personal , Emociones/fisiología , Distrés Psicológico , Afecto/fisiologíaRESUMEN
Background: Latency reversing agents (LRAs) such as protein kinase C (PKC) modulators can reduce rebound-competent HIV reservoirs in small animal models. Furthermore, administration of natural killer (NK) cells following LRA treatment improves this reservoir reduction. It is currently unknown why the combination of a PKC modulator and NK cells is so potent and whether exposure to PKC modulators may augment NK cell function in some way. Methods: Primary human NK cells were treated with PKC modulators (bryostatin-1, prostratin, or the designed, synthetic bryostatin-1 analog SUW133), and evaluated by examining expression of activation markers by flow cytometry, analyzing transcriptomic profiles by RNA sequencing, measuring cytotoxicity by co-culturing with K562 cells, assessing cytokine production by Luminex assay, and examining the ability of cytokines and secreted factors to independently reverse HIV latency by co-culturing with Jurkat-Latency (J-Lat) cells. Results: PKC modulators increased expression of proteins involved in NK cell activation. Transcriptomic profiles from PKC-treated NK cells displayed signatures of cellular activation and enrichment of genes associated with the NFκB pathway. NK cell cytotoxicity was unaffected by prostratin but significantly decreased by bryostatin-1 and SUW133. Cytokines from PKC-stimulated NK cells did not induce latency reversal in J-Lat cell lines. Conclusions: Although PKC modulators have some significant effects on NK cells, their contribution in "kick and kill" strategies is likely due to upregulating HIV expression in CD4+ T cells, not directly enhancing the effector functions of NK cells. This suggests that PKC modulators are primarily augmenting the "kick" rather than the "kill" arm of this HIV cure approach.
RESUMEN
The objective of the present study was to evaluate the interdependency of parent-adolescent inflammation trends across time and to examine whether shared family socioeconomic characteristics explained between-family differences in parents' and adolescents' risk for inflammation. A total of N = 348 families, consisting of one parent and one adolescent child, were followed every two years in a three-wave longitudinal study. Sociodemographic questionnaires were used to determine parental educational attainment and family income-to-needs ratio (INR). At each time point, parents and adolescents collected dried blood spot (DBS) samples that were assayed for circulating CRP and log-transformed prior to analysis by longitudinal dyadic models. Models revealed significant differences in parents' and adolescents' inflammation trends over time (bint = - 0.13, p < 0.001). While parental CRP levels remained relatively stable across the study period, adolescent CRP increased by approximately 38% between study waves. Parents' average CRP levels were positively correlated with adolescents' average CRP (r = 0.32, p < 0.001), but parental change in CRP over time was not significantly related to change in adolescents' CRP over time. Family dyads with higher parental educational attainment had lower average CRP (b = -0.08, p = 0.01), but parental education did not predict change in dyads' inflammation over time. Study findings suggest that shared family socioeconomic characteristics contribute to baseline similarities in parents' and adolescents' inflammation and potentially point to adolescence as a period of inflammatory change where youth may diverge from parental inflammation trends.
RESUMEN
Having associations with a range of adverse physical health outcomes including mortality, loneliness is increasingly recognized as a pressing public health concern, but the mechanisms studied to date do not yet explain all loneliness-related health risk. We sought to evaluate whether epigenetic influences on DNA methylation could help explain the relationship between loneliness and health. To do so, we first estimated associations between loneliness and epigenetic age acceleration (EAA) in a subsample of participants in the study of midlife in the United States (n = 1,310), before testing whether EAA mediated and/or moderated the association between loneliness and the onset of chronic health conditions in older adulthood (n = 445 completing longitudinal follow-ups). Greater loneliness was weakly associated with greater EAA in the Horvath, DunedinPACE, and GrimAge measures after accounting for demographic (0.08 ≤ ß ≤ 0.11) and behavioral (0.06 ≤ ß ≤ 0.08) covariates. Loneliness also predicted increases in chronic condition counts and these effects were more pronounced for individuals with higher DunedinPACE EAA values (interaction term ß = 0.09, p = .009), suggesting possible synergistic impacts. EAA measures appear to be promising in helping to understand individual variations in the health impacts of loneliness, but the specific mechanisms involved require further research. (PsycInfo Database Record (c) 2024 APA, all rights reserved).
Asunto(s)
Metilación de ADN , Epigénesis Genética , Soledad , Humanos , Soledad/psicología , Masculino , Femenino , Enfermedad Crónica , Persona de Mediana Edad , Anciano , Estudios Longitudinales , Envejecimiento/psicología , Envejecimiento/fisiología , Adulto , Estados UnidosRESUMEN
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.
Asunto(s)
Ansiedad , Cuidadores , Depresión , Trasplante de Células Madre Hematopoyéticas , Mieloma Múltiple , Psiconeuroinmunología , Trasplante Autólogo , Humanos , Trasplante de Células Madre Hematopoyéticas/psicología , Trasplante de Células Madre Hematopoyéticas/métodos , Mieloma Múltiple/inmunología , Mieloma Múltiple/psicología , Mieloma Múltiple/terapia , Cuidadores/psicología , Depresión/inmunología , Depresión/psicología , Estrés Psicológico/inmunología , Estrés Psicológico/psicología , Envejecimiento/inmunología , Envejecimiento/psicología , Calidad de Vida/psicologíaRESUMEN
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.
Asunto(s)
Neoplasias de la Mama , Humanos , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Femenino , Persona de Mediana Edad , Características de la Residencia , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Pronóstico , Anciano , Adulto , Estudios ProspectivosRESUMEN
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.
Asunto(s)
Neoplasias de la Mama , Humanos , Femenino , Neoplasias de la Mama/cirugía , Intervención Psicosocial , Biomarcadores , Adrenérgicos , CogniciónRESUMEN
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.
Asunto(s)
Neoplasias de la Mama , Interferón Tipo I , Humanos , Femenino , Neoplasias de la Mama/complicaciones , ARN , Fatiga/genética , Inflamación/complicacionesRESUMEN
Childhood maltreatment has been repeatedly linked to a higher incidence of health conditions with an underlying proinflammatory component, such as asthma, chronic obstructive pulmonary disease, stroke, and cardiovascular disease. Childhood maltreatment has also been linked to elevated systemic inflammation prior to the onset of disease. However, childhood maltreatment is highly comorbid with other risk factors which have also been linked to inflammation, namely major depression. The present analysis addresses this issue by assessing the association of maltreatment with genome-wide transcriptional profiling of immune cells collected from four orthogonal groups of adolescents (aged 13-17): maltreated and not maltreated in childhood, with and without major depressive disorder. Maltreatment and psychiatric history were determined using semi-structured clinical interviews and cross-validated using self-report questionnaires. Dried whole blood spots were collected from each participant (n = 133) and assayed to determine the extent to which maltreatment in childhood was associated with a higher prevalence of transcriptional activity among differentially expressed genes, specific immune cell subtypes, and up- or down-regulation of genes involved in immune function after accounting for current major depression. Maltreatment was associated with increased interferon regulatory factor (IRF) transcriptional activity (p = 0.03), as well as nuclear factor erythroid-2 related factor 1 (NRF1; p = 0.002) and MAF (p = 0.01) among up-regulated genes, and increased activity of nuclear factor kappa beta (NF-κB) among down-regulated genes (p = 0.01). Non-classical CD16+ monocytes were implicated in both the up- and down-regulated genes among maltreated adolescents. These data provide convergent evidence supporting the role of maltreatment in altering intracellular and molecular markers of immune function, as well as implicate monocyte/macrophage functions as mechanisms through which childhood maltreatment may shape lifelong immune development and function.
Asunto(s)
Maltrato a los Niños , Trastorno Depresivo Mayor , Humanos , Adolescente , Niño , Trastorno Depresivo Mayor/genética , Monocitos , Inflamación , Perfilación de la Expresión Génica , Maltrato a los Niños/psicologíaRESUMEN
Experimental activation of the innate immune system has contributed significantly to both our understanding of how psychological factors influence immune function as well as how immune activity influences the brain and behavior. The annual influenza vaccine can be used to interrogate the effects of mild immune stimulation on day-to-day changes in psychological processes in human subjects that range across the lifespan and in both clinical and non-clinical populations. Yet, the immune response to the influenza vaccine in the days immediately following its administration are not well characterized. The present study describes changes in inflammatory and antiviral gene expression within circulating immune cells, plasma cytokines, and C-reactive protein (CRP) following receipt of the flu vaccine, and further reports the association between several common behavioral health factors and the acute immune response. Participants were 65 adults (mean age 18.81 ± 1.03 years; 66.2% female) who provided a blood sample immediately before and then 24 h after receiving the vaccine. A subsample also provided additional blood samples at 48 and 72 h. Plasma was assayed for CRP, IL-6, IL-10, IL-8, TNF-α, and IFN-γ, and peripheral blood mononuclear cell RNA was sequenced for evidence of change in expression of an a priori set of type 1 interferon (IFN) and inflammatory response genes (INFLAM). Plasma cytokines, CRP, and IFN response genes increased 24 h after vaccination, all ps < .001. The increase in IFN gene expression correlated with the observed increase in plasma cytokines and CRP, p < .0001. The immune response to influenza vaccination at 24-hours was moderated by anxiety symptoms, BMI, being female, sleep, and history of influenza vaccination. These factors and their associations with common immune challenges may be useful in studies interrogating the origins of immune dysregulation. The annual influenza vaccine is an accessible and reliable exogenous activator of both circulating and transcriptional markers of innate immune reactivity, with sensitivity to behavioral health factors relevant for psychoneuroimmunology research.
Asunto(s)
Vacunas contra la Influenza , Gripe Humana , Adulto , Humanos , Femenino , Adolescente , Adulto Joven , Masculino , Gripe Humana/prevención & control , Leucocitos Mononucleares/metabolismo , Citocinas , Inmunidad Innata , Vacunación , Anticuerpos AntiviralesRESUMEN
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.
Asunto(s)
Envejecimiento , Jubilación , Niño , Humanos , Anciano , Envejecimiento/genética , Relaciones Interpersonales , Amigos , Epigénesis Genética/genética , Metilación de ADN/genéticaRESUMEN
Patient-reported outcomes (PROs) capture subjective social determinants of health (SDOHs), which can affect health outcomes through the stress response pathway. The conserved transcriptional response to adversity (CTRA) is a stress-mediated proinflammatory transcriptomic pattern that has been linked to adverse hematopoietic cell transplant (HCT) outcomes. This study examined the association of pretransplant CTRA with patient-reported SDOHs in allogeneic HCT recipients. In this cross-sectional study, pre-HCT SDOH-related PROs included the 36-Item Short Form Health Survey and the Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT). CTRA was assessed by RNA sequencing of whole blood specimens, with mixed effects linear regression models relating CTRA expression to PRO scores while controlling for age, sex, race, disease, and performance status. Among 121 patients, the median age was 54 years, 42% were female, and 91% were White. CTRA was elevated in participants reporting lower scores on the FACT-BMT (P = .003), including the general (P = .003) and BMT-specific (P = .014) components. Effects were driven by the social well-being domain (P = .0001). This corresponded to an 8% to 15% difference in CTRA RNA expression across a 4 standard deviation range in patient-reported SDOHs. Ancillary bioinformatics analyses confirmed the association of well-being with reduced proinflammatory transcription pathway activity [cyclic AMP response element-binding protein, (CREB), NF-κB, and activating protein-1 (AP-1)]. In conclusion, HCT-treated patients who experience unfavorable social conditions show elevated CTRA expression in pretransplant blood samples. These data highlight the biologic sequelae of social well-being and community context and suggest a potential molecular mechanism for the impact of social gradients in HCT outcomes. Targeting this pathway could optimize outcomes in this high-risk population.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Transcriptoma , Humanos , Femenino , Persona de Mediana Edad , Masculino , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Estudios Transversales , Perfilación de la Expresión Génica , Encuestas y CuestionariosRESUMEN
INTRODUCTION: Adverse psychosocial exposure is associated with increased proinflammatory gene expression and reduced type-1 interferon gene expression, a profile known as the conserved transcriptional response to adversity (CTRA). Little is known about CTRA activity in the context of cognitive impairment, although chronic inflammatory activation has been posited as one mechanism contributing to late-life cognitive decline. METHODS: We studied 171 community-dwelling older adults from the Wake Forest Alzheimer's Disease Research Center who answered questions via a telephone questionnaire battery about their perceived stress, loneliness, well-being, and impact of COVID-19 on their life, and who provided a self-collected dried blood spot sample. Of those, 148 had adequate samples for mRNA analysis, and 143 were included in the final analysis, which including participants adjudicated as having normal cognition (NC, n = 91) or mild cognitive impairment (MCI, n = 52) were included in the analysis. Mixed effect linear models were used to quantify associations between psychosocial variables and CTRA gene expression. RESULTS: In both NC and MCI groups, eudaimonic well-being (typically associated with a sense of purpose) was inversely associated with CTRA gene expression whereas hedonic well-being (typically associated with pleasure seeking) was positively associated. In participants with NC, coping through social support was associated with lower CTRA gene expression, whereas coping by distraction and reframing was associated with higher CTRA gene expression. CTRA gene expression was not related to coping strategies for participants with MCI, or to either loneliness or perceived stress in either group. DISCUSSION: Eudaimonic and hedonic well-being remain important correlates of molecular markers of stress, even in people with MCI. However, prodromal cognitive decline appears to moderate the significance of coping strategies as a correlate of CTRA gene expression. These results suggest that MCI can selectively alter biobehavioral interactions in ways that could potentially affect the rate of future cognitive decline and may serve as targets for future intervention efforts.
RESUMEN
Background: Early-life adversity (ELA) has been linked to higher depression risk across the life span and chronic inflammatory conditions that contribute to earlier mortality. In this study, we characterized innate immune responses to acute social stress in a community sample of adolescents (mean age = 13.9 ± 1.6 years; 46.4% female) as a potential pathway linking ELA and depression pathogenesis. Methods: Parents reported their child's exposure to 9 ELAs, and adolescents participated in the Trier Social Stress Test for Children, with blood collected immediately before and then at 60 and 90 minutes thereafter. Overall, 65 adolescents had complete data for analysis of stress-induced changes in gene expression and 84 adolescents had complete data for circulating inflammatory markers. Results: Relative to adolescents exposed to no ELA (11.9%) or low ELA (ELA = 1-3; 67.9%), those exposed to high ELA (ELA = 4+; 20.2%) showed larger stress-associated increases in expression of both proinflammatory and innate antiviral gene transcripts in circulating blood. Consistent with a potential mediating role of sympathetic nervous system activity, promoter-based bioinformatics analyses implicated CREB transcription factor activity in structuring observed gene expression differences. These effects were accompanied by a smaller initial but protracted increase in circulating interleukin 6 in adolescents with high ELA. Conclusions: Results are consistent with the hypothesis that ELA may enhance cellular and gene regulatory reactivity to stress, which may, in turn, increase vulnerability to depression and other inflammation-related disease processes.
RESUMEN
Alterations in immune system gene expression have been implicated in psychopathology, but it remains unclear whether similar associations occur for intraindividual variations in emotion. The present study examined whether positive emotion and negative emotion were related to expression of pro-inflammatory and antiviral genes in circulating leukocytes from a community sample of 90 adolescents (Mage = 16.3 years, SD = 0.7; 51.1% female). Adolescents reported their positive emotion and negative emotion and provided blood samples twice, five weeks apart. Using a multilevel analytic framework, we found that within-individual increases in positive emotion were associated with reduced expression of both pro-inflammatory and Type I interferon (IFN) response genes, even after adjusting for demographic and biological covariates, and for leukocyte subset abundance. By contrast, increases in negative emotion were related to higher expression of pro-inflammatory and Type I IFN genes. When tested in the same model, only associations with positive emotion emerged as significant, and increases in overall emotional valence were associated with both lower pro-inflammatory and antiviral gene expression. These results are distinct from the previously observed Conserved Transcriptional Response to Adversity (CTRA) gene regulation pattern characterized by reciprocal changes in pro-inflammatory and antiviral gene expression and may reflect alterations in generalized immunologic activation. These findings highlight one biological pathway by which emotion may potentially impact health and physiological function in the context of the immune system, and future studies can investigate whether fostering positive emotion may promote adolescent health through changes in the immune system.
Asunto(s)
Emociones , Transcriptoma , Adolescente , Humanos , Femenino , Masculino , Activación Transcripcional , Emociones/fisiología , Regulación de la Expresión Génica , AntiviralesRESUMEN
Beta-adrenergic blockade has been associated with improved cancer survival in patients with triple-negative breast cancer (TNBC), but the mechanisms of these effects remain unclear. In clinical epidemiological analyses, we identified a relationship between beta-blocker use and anthracycline chemotherapy in protecting against TNBC progression, disease recurrence, and mortality. We recapitulated the effect of beta-blockade on anthracycline efficacy in xenograft mouse models of TNBC. In metastatic 4T1.2 and MDA-MB-231 mouse models of TNBC, beta-blockade improved the efficacy of the anthracycline doxorubicin by reducing metastatic development. We found that anthracycline chemotherapy alone, in the absence of beta-blockade, increased sympathetic nerve fiber activity and norepinephrine concentration in mammary tumors through the induction of nerve growth factor (NGF) by tumor cells. Moreover, using preclinical models and clinical samples, we found that anthracycline chemotherapy up-regulated ß2-adrenoceptor expression and amplified receptor signaling in tumor cells. Neurotoxin inhibition of sympathetic neural signaling in mammary tumors using 6-hydroxydopamine or genetic deletion of NGF or ß2-adrenoceptor in tumor cells enhanced the therapeutic effect of anthracycline chemotherapy by reducing metastasis in xenograft mouse models. These findings reveal a neuromodulatory effect of anthracycline chemotherapy that undermines its potential therapeutic impact, which can be overcome by inhibiting ß2-adrenergic signaling in the tumor microenvironment. Supplementing anthracycline chemotherapy with adjunctive ß2-adrenergic antagonists represents a potential therapeutic strategy for enhancing the clinical management of TNBC.
Asunto(s)
Antraciclinas , Neoplasias de la Mama Triple Negativas , Humanos , Animales , Ratones , Antraciclinas/farmacología , Antraciclinas/uso terapéutico , Neoplasias de la Mama Triple Negativas/genética , Factor de Crecimiento Nervioso/uso terapéutico , Línea Celular Tumoral , Recurrencia Local de Neoplasia/tratamiento farmacológico , Receptores Adrenérgicos/uso terapéutico , Microambiente TumoralRESUMEN
Marital quality shares ties to inflammation-related conditions like cardiovascular disease and diabetes. Lab-based studies implicate hostility during marital conflict as a mechanism via inflammatory reactivity, but little attention has been paid to the inflammatory aftermath of other marital exchanges. A spouse's emotional distress is an important but overlooked context for middle-aged and older couples, as conflict declines and networks shrink. To examine the links of spousal distress to changes in proinflammatory gene expression, 38 adults ages 40-81 witnessed their spouse relive an upsetting personal memory aloud, rated their mood before and after, and provided blood samples at baseline and twice post-task; they also shared their own upsetting memory and discussed a marital problem in the interim. Those whose spouse disclosed their upsetting memory with greater emotional intensity showed larger elevations in proinflammatory gene expression 30-40 min and 80-90 min after the task. The association replicated for listeners whose negative mood increased more in response to spousal disclosure. Findings were robust to behavior in the other emotional tasks, race, gender, age, alcohol, smoking, comorbidities, and sagittal abdominal diameter. These novel results identify spousal distress as a key marital context that may escalate inflammation-related health risks.
Asunto(s)
Matrimonio , Esposos , Adulto , Persona de Mediana Edad , Humanos , Anciano , Esposos/psicología , Matrimonio/psicología , Conflicto Familiar/psicología , Inflamación , Expresión GénicaRESUMEN
Slow paced breathing via heart rate variability (HRV) biofeedback stimulates vagus-nerve pathways that counter noradrenergic stress and arousal pathways that can influence production and clearance of Alzheimer's disease (AD)-related proteins. Thus, we examined whether HRV biofeedback intervention affects plasma Αß40, Αß42, total tau (tTau), and phosphorylated tau-181 (pTau-181) levels. We randomized healthy adults (N = 108) to use slow-paced breathing with HRV biofeedback to increase heart rate oscillations (Osc+) or to use personalized strategies with HRV biofeedback to decrease heart rate oscillations (Osc-). They practiced 20-40 min daily. Four weeks of practicing the Osc+ and Osc- conditions produced large effect size differences in change in plasma Aß40 and Aß42 levels. The Osc+ condition decreased plasma Αß while the Osc- condition increased Αß. Decreases in Αß were associated with decreases in gene transcription indicators of ß-adrenergic signaling, linking effects to the noradrenergic system. There were also opposing effects of the Osc+ and Osc- interventions on tTau for younger adults and pTau-181 for older adults. These results provide novel data supporting a causal role of autonomic activity in modulating plasma AD-related biomarkers.Trial registration: NCT03458910 (ClinicalTrials.gov); first posted on 03/08/2018.
Asunto(s)
Enfermedad de Alzheimer , Péptidos beta-Amiloides , Humanos , Anciano , Frecuencia Cardíaca/fisiología , Enfermedad de Alzheimer/genética , Proteínas tau/metabolismo , Sistema Nervioso Autónomo/fisiología , Nervio Vago/metabolismo , BiomarcadoresRESUMEN
Late life insomnia may increase risk for accelerated biological aging. Intervening to treat insomnia may provide protection from biological aging by reducing the prevalence of senescent cells in the immune system, as indicated by gene expression of a marker of cellular senescence, p16INK4a. In the present study, we determine whether treatment of insomnia in older adults with cognitive behavioral therapy for insomnia (CBT-I) would reduce p16INK4a gene expression in peripheral blood mononuclear cells (PBMC), compared to a sleep education therapy (SET), an active comparator condition. Secondly, we investigate the relationship between sustained insomnia remission and reduced expression of p16INK4a. Participants 60 + years old with insomnia were enrolled in a randomized controlled trial and assigned to CBT-I or SET. Analyses of 231 older adults (CBT-I = 119; SET = 112) examine baseline, post (2 months), and 24 months gene expression of p16INK4a. Compared to baseline, expression of p16INK4a increased in the SET group over 24 months (P = 0.03), but showed no change in the CBT-I group. Those who received CBT-I and experienced sustained remission of insomnia had a significant decline in p16INK4a expression by 24 months compared to baseline (P = 0.02). Individuals not sustaining remission of insomnia exhibited overall increase expression of p16INK4a by 24 months (P = 0.03). In older adults with insomnia, p16INK4a increases over 24 months, while CBT-I treatment of insomnia mitigates the increase in p16INK4a. Further, sustained remission of insomnia using CBT-I leads to a decrease in p16INK4a. These results suggest that behavioral interventions that are effective at treating insomnia might reduce the population of senescent cells in circulating blood.