Clinical outcomes among allogeneic hematopoietic cell transplant (HCT) recipients are negatively affected by low socioeconomic status (SES), yet the biological mechanisms accounting for this health ...disparity remain to be elucidated. Among unrelated donor HCT recipients with acute myelogenous leukemia, one recent pilot study linked low SES to increased expression of a stress-related gene expression profile known as the conserved transcriptional response to adversity (CTRA) in peripheral blood mononuclear cells, which involves up-regulation of pro-inflammatory genes and down-regulation of genes involved in type I interferon response and antibody synthesis.
This study examined these relationships using additional measures in a larger archival sample of 261 adults who received an unrelated donor HCT for acute myelogenous leukemia to 1) identify cellular and molecular mechanisms involved in SES-related differences in pre-transplant leukocyte transcriptome profiles, and 2) evaluate pre-transplant CTRA biology associations with clinical outcomes through multivariable analysis controlling for demographic-, disease-, and transplant-related covariates.
Low SES individuals showed increases in classic monocyte activation and pro-inflammatory transcription control pathways as well as decreases in activation of nonclassic monocytes, all consistent with the CTRA biological pattern. Transplant recipients in the highest or lowest quartiles of the CTRA pro-inflammatory gene component had a more than 2-fold elevated hazard of relapse (hazard ratio HR = 2.47, 95% confidence interval CI = 1.44 to 4.24),
= .001; HR = 2.52, 95% CI = 1.46 to 4.34,
= .001) and more than 20% reduction in leukemia-free survival (HR = 1.57, 95% CI = 1.08 to 2.28,
= .012; HR = 1.49, 95% CI = 1.04 to 2.15,
= .03) compared with the middle quartiles.
These findings identify SES- and CTRA-associated myeloid- and inflammation-related transcriptome signatures in recipient pre-transplant blood samples as a potential novel predictive biomarker of HCT-related clinical outcomes.
To combine social genomics with cultural approaches to expand understandings of the somatic health dynamics of online gaming, including in the controversial nosological construct of internet gaming ...disorder (IGD).
In blood samples from 56 U.S. gamers, we examined expression of the conserved transcriptional response to adversity (CTRA), a leukocyte gene expression profile activated by chronic stress. We compared positively engaged and problem gamers, as identified by an ethnographically developed measure, the Positive and Negative Gaming Experiences Scale (PNGE-42), and also by a clinically derived IGD scale (IGDS-SF9).
CTRA profiles showed a clear relationship with PNGE-42, with a substantial linkage to offline social support, but were not meaningfully associated with disordered play as measured by IGDS-SF9.
Our study advances understanding of the psychobiology of play, demonstrating via novel transcriptomic methods the association of negatively experienced internet play with biological measures of chronic threat, uncertainty, and distress. Our findings are consistent with the view that problematic patterns of online gaming are a proxy for broader patterns of biopsychosocial stress and distress such as loneliness, rather than a psychiatric disorder sui generis, which might exist apart from gamers' other life problems. By confirming the biological correlates of certain patterns of internet gaming, culturally-sensitive genomics approaches such as this can inform both evolutionary theorizing regarding the nature of play, as well as current psychiatric debates about the appropriateness of modeling distressful gaming on substance addiction and problem gambling.
Genome-wide transcriptional profiling has emerged as a powerful tool for analyzing biological mechanisms underlying social gradients in health, but utilization in population-based studies has been ...hampered by logistical constraints and costs associated with venipuncture blood sampling. Dried blood spots (DBS) provide a minimally invasive, low-cost alternative to venipuncture, and in this article we evaluate how closely the substantive results from DBS transcriptional profiling correspond to those derived from parallel analyses of gold-standard venous blood samples (PAXgene whole blood and peripheral blood mononuclear cells PBMC). Analyses focused on differences in gene expression between African-Americans and Caucasians in a community sample of 82 healthy adults (age 18-70 years; mean 35). Across 19,679 named gene transcripts, DBS-derived values correlated r = .85 with both PAXgene and PBMC values. Results from bioinformatics analyses of gene expression derived from DBS samples were concordant with PAXgene and PBMC samples in identifying increased Type I interferon signaling and up-regulated activity of monocytes and natural killer (NK) cells in African-Americans compared to Caucasian participants. These findings demonstrate the feasibility of DBS in field-based studies of gene expression and encourage future studies of human transcriptome dynamics in larger, more representative samples than are possible with clinic- or lab-based research designs.
•β-adrenergic-induced C/EBPβ activity up-regulated Arg1 expression in macrophages.•Knockdown of Cebpb inhibited β-adrenergic induction of C/EBPβ nuclear protein.•RNAseq analysis identified 20 ...additional β-adrenergic-C/EBPβ-regulated M2 genes.
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.
Stress can alter immunological, neurochemical and endocrinological functions, but its role in cancer progression is not well understood. Here, we show that chronic behavioral stress results in higher ...levels of tissue catecholamines, greater tumor burden and more invasive growth of ovarian carcinoma cells in an orthotopic mouse model. These effects are mediated primarily through activation of the tumor cell cyclic AMP (cAMP)-protein kinase A (PKA) signaling pathway by the β2 adrenergic receptor (encoded by ADRB2). Tumors in stressed animals showed markedly increased vascularization and enhanced expression of VEGF, MMP2 and MMP9, and we found that angiogenic processes mediated the effects of stress on tumor growth in vivo. These data identify β-adrenergic activation of the cAMP-PKA signaling pathway as a major mechanism by which behavioral stress can enhance tumor angiogenesis in vivo and thereby promote malignant cell growth. These data also suggest that blocking ADRB-mediated angiogenesis could have therapeutic implications for the management of ovarian cancer.
There is growing evidence that chronic stress and other behavioral conditions are associated with cancer pathogenesis and progression, but the mechanisms involved in this association are poorly ...understood. We examined the effects of two mediators of stress, norepinephrine and epinephrine, on the activation of signal transducer and activator of transcription-3 (STAT3), a transcription factor that contributes to many promalignant pathways. Exposure of ovarian cancer cell lines to increasing concentrations of norepinephrine or epinephrine showed that both independently increased levels of phosphorylated STAT3 in a dose-dependent fashion. Immunolocalization and ELISA of nuclear extracts confirmed increased nuclear STAT3 in response to norepinephrine. Activation of STAT3 was inhibited by blockade of the beta1- and beta2-adrenergic receptors with propranolol, and by blocking protein kinase A with KT5720, but not with the alpha receptor blockers prazosin (alpha1) and/or yohimbine (alpha2). Catecholamine-mediated STAT3 activation was not inhibited by pretreatment with an anti-interleukin 6 (IL-6) antibody or with small interfering RNA (siRNA)-mediated decrease in IL-6 or gp130. Regarding the effects of STAT3 activation, exposure to norepinephrine resulted in an increase in invasion and matrix metalloproteinase (MMP-2 and MMP-9) production. These effects were completely blocked by STAT3-targeting siRNA. In mice, treatment with liposome-incorporated siRNA directed against STAT3 significantly reduced isoproterenol-stimulated tumor growth. These studies show IL-6-independent activation of STAT3 by norepinephrine and epinephrine, proceeding through the beta1/beta2-adrenergic receptors and protein kinase A, resulting in increased matrix metalloproteinase production, invasion, and in vivo tumor growth, which can be ameliorated by the down-regulation of STAT3.
Recent studies have demonstrated that chronic stress promotes tumor growth, angiogenesis, and metastasis. In ovarian cancer, levels of the pro-angiogenic cytokine, interleukin 6 (IL-6), are known to ...be elevated in individuals experiencing chronic stress, but the mechanism(s) by which this cytokine is regulated and its role in tumor growth remain under investigation. Here we show that stress hormones such as norepinephrine lead to increased expression of IL-6 mRNA and protein levels in ovarian carcinoma cells. Furthermore, we demonstrate that norepinephrine stimulation activates Src tyrosine kinase and this activation is required for increased IL-6 expression. These results demonstrate that stress hormones activate signaling pathways known to be critical in ovarian tumor progression.
Across a variety of adverse life circumstances, such as social isolation and low socioeconomic status, mammalian immune cells have been found to show a conserved transcriptional response to adversity ...(CTRA) involving increased expression of proinflammatory genes. The present study examines whether such effects might stem in part from the selective up-regulation of a subpopulation of immature proinflammatory monocytes (... in mice, ... in humans) within the circulating leukocyte pool. Transcriptome representation analyses showed relative expansion of the immature proinflammatory monocyte transcriptome in peripheral blood mononuclear cells from people subject to chronic social stress (low socioeconomic status) and mice subject to repeated social defeat. Cellular dissection of the mouse peripheral blood mononuclear cell transcriptome confirmed these results, and promoter-based bioinformatic analyses indicated increased activity of transcription factors involved in early myeloid lineage differentiation and proinflammatory effector function (PU.1, NF-kB, EGR1, MZF1, NRF2). Analysis of bone marrow hematopoiesis confirmed increased myelopoietic output of ... monocytes and ... granulocytes in mice subject to repeated social defeat, and these effects were blocked by pharmacologic antagonists of β-adrenoreceptors and the myelopoietic growth factor GM-CSF. These results suggest that sympathetic nervous system-induced up-regulation of myelopoiesis mediates the proinflammatory component of the leukocyte CTRA dynamic and may contribute to the increased risk of inflammation-related disease associated with adverse social conditions. (ProQuest: ... denotes formulae/symbols omitted.)
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