Steve W. Cole

A Video Game Improves Behavioral Outcomes in Adolescents and Young Adults With Cancer: A Randomized Trial

OBJECTIVE. Suboptimal adherence to self-administered medications is a common problem. The purpose of this study was to determine the effectiveness of a video-game intervention for improving adherence and other behavioral outcomes for adolescents and young adults with malignancies including acute leukemia, lymphoma, and soft-tissue sarcoma. METHODS. A randomized trial with baseline and 1- and 3-month assessments was conducted from 2004 to 2005 at 34 medical centers in the United States, Canada, and Australia. A total of 375 male and female patients who were 13 to 29 years old, had an initial or relapse diagnosis of a malignancy, and currently undergoing treatment and expected to continue treatment for at least 4 months from baseline assessment were randomly assigned to the intervention or control group. The intervention was a video game that addressed issues of cancer treatment and care for teenagers and young adults. Outcome measures included adherence, self-efficacy, knowledge, control, stress, and quality of life. For patients who were prescribed prophylactic antibiotics, adherence to trimethoprim-sulfamethoxazole was tracked by electronic pill-monitoring devices (n = 200). Adherence to 6-mercaptopurine was assessed through serum metabolite assays (n = 54). RESULTS. Adherence to trimethoprim-sulfamethoxazole and 6-mercaptopurine was greater in the intervention group. Self-efficacy and knowledge also increased in the intervention group compared with the control group. The intervention did not affect self-report measures of adherence, stress, control, or quality of life. CONCLUSIONS. The video-game intervention significantly improved treatment adherence and indicators of cancer-related self-efficacy and knowledge in adolescents and young adults who were undergoing cancer therapy. The findings support current efforts to develop effective video-game interventions for education and training in health care.

Social regulation of gene expression in human leukocytes

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

Promoter CpG Methylation Contributes to ES Cell Gene Regulation in Parallel with Oct4/Nanog, PcG Complex, and Histone H3 K4/K27 Trimethylation

We report here genome-wide mapping of DNA methylation patterns at proximal promoter regions in mouse embryonic stem (mES) cells. Most methylated genes are differentiation associated and repressed in mES cells. By contrast, the unmethylated gene set includes many housekeeping and pluripotency genes. By crossreferencing methylation patterns to genome-wide mapping of histone H3 lysine (K) 4/27 trimethylation and binding of Oct4, Nanog, and Polycomb proteins on gene promoters, we found that promoter DNA methylation is the only marker of this group present on approximately 30% of genes, many of which are silenced in mES cells. In demethylated mutant mES cells, we saw upregulation of a subset of X-linked genes and developmental genes that are methylated in wild-type mES cells, but lack either H3K4 and H3K27 trimethylation or association with Polycomb, Oct4, or Nanog. Our data suggest that in mES cells promoter methylation represents a unique epigenetic program that complements other regulatory mechanisms to ensure appropriate gene expression.

Elevated Physical Health Risk Among Gay Men Who Conceal Their Homosexual Identity

This study examined the incidence of infectious and neoplastic diseases among 222 HIV-seronegative gay men who participated in the Natural History of AIDS Psychosocial Study. Those who concealed the expression of their homosexual identity experienced a significantly higher incidence of cancer (odds ratio = 3.18) and several infectious diseases (pneumonia, bronchitis, sinusitis, and tuberculosis; odds ratio = 2.91) over a 5-year follow-up period. These effects could not be attributed to differences in age, ethnicity, socioeconomic status, repressive coping style, health-relevant behavioral patterns (e.g., drug use, exercise), anxiety, depression, or reporting biases (e.g., negative affectivity, social desirability). Results are interpreted in the context of previous data linking concealed homosexual identity to other physical health outcomes (e.g., HIV progression and psychosomatic symptomatology) and theories linking psychological inhibition to physical illness.

Inflammatory Biomarkers for Persistent Fatigue in Breast Cancer Survivors

Purpose: This study seeks to define immunologic and inflammatory variables associated with persistent post-treatment fatigue in breast cancer survivors. Experimental Design: Leukocyte subsets, plasma inflammatory markers, and ex vivo proinflammatory cytokine production were assessed in 50 fatigued and nonfatigued breast cancer survivors recruited ≥2 years after successful primary therapy. Multivariate statistical analyses were used to define a composite immunologic biomarker of fatigue risk. Results: Fatigued breast cancer survivors were distinguished from nonfatigued survivors by increased ex vivo monocyte production of interleukin (IL)-6 and tumor necrosis factor-α following lipopolysaccharide stimulation, elevated plasma IL-1ra and soluble IL-6 receptor (sIL-6R/CD126), decreased monocyte cell-surface IL-6R, and decreased frequencies of activated T lymphocytes and myeloid dendritic cells in peripheral blood (all P < 0.05). An inverse correlation between sIL-6R and cell-surface IL-6R was consistent with inflammation-mediated shedding of IL-6R, and in vitro studies confirmed that proinflammatory cytokines induced such shedding. Multivariate linear discriminant function analysis identified two immunologic markers, the ratio of sIL-6R to monocyte-associated IL-6R and decreased circulating CD69+ T lymphocytes, as highly diagnostic of fatigue (P = 0.0005), with cross-validation estimates indicating 87% classification accuracy (sensitivity = 0.83; specificity = 0.83). Conclusion: These results extend links between fatigue and inflammatory markers to show a functional alteration in proinflammatory cytokine response to lipopolysaccharide and define a prognostic biomarker of behavioral fatigue.

Inflammation and Behavioral Symptoms After Breast Cancer Treatment: Do Fatigue, Depression, and Sleep Disturbance Share a Common Underlying Mechanism?

PURPOSE Fatigue, depression, and sleep disturbance are common adverse effects of cancer treatment and frequently co-occur. However, the possibility that inflammatory processes may underlie this constellation of symptoms has not been examined. PATIENTS AND METHODS Women (N = 103) who had recently finished primary treatment (ie, surgery, radiation, chemotherapy) for early-stage breast cancer completed self-report scales and provided blood samples for determination of plasma levels of inflammatory markers: soluble tumor necrosis factor (TNF) receptor II (sTNF-RII), interleukin-1 receptor antagonist, and C-reactive protein. RESULTS Symptoms were elevated at the end of treatment; greater than 60% of participants reported clinically significant problems with fatigue and sleep, and 25% reported elevated depressive symptoms. Women treated with chemotherapy endorsed higher levels of all symptoms and also had higher plasma levels of sTNF-RII than women who did not receive chemotherapy (all P < .05). Fatigue was positively associated with sTNF-RII, particularly in the chemotherapy-treated group (P < .05). Depressive symptoms and sleep problems were correlated with fatigue but not with inflammatory markers. CONCLUSION This study confirms high rates of behavioral symptoms in breast cancer survivors, particularly those treated with chemotherapy, and indicates a role for TNF-α signaling as a contributor to postchemotherapy fatigue. Results also suggest that fatigue, sleep disturbance, and depression may stem from distinct biologic processes in post-treatment survivors, with inflammatory signaling contributing relatively specifically to fatigue.

Sleep Loss Activates Cellular Inflammatory Signaling

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

Maternal warmth buffers the effects of low early-life socioeconomic status on pro-inflammatory signaling in adulthood.

The notion that family support may buffer individuals under adversity from poor outcomes has been theorized to have important implications for mental and physical health, but little is known about the biological mechanisms that explain these links. We hypothesized that adults who grew up in low socioeconomic status (SES) households but who experienced high levels of maternal warmth would be protected from the pro-inflammatory states typically associated with low SES. A total of 53 healthy adults (aged 25–40 years) low in SES early in life were assessed on markers of immune activation and systemic inflammation. Genome-wide transcriptional profiling also was conducted. Low early-life SES individuals who had mothers, who expressed high warmth toward them, exhibited less Toll-like receptor-stimulated production of interleukin 6, and reduced bioinformatic indications of pro-inflammatory transcription factor activity (NF-κB) and immune activating transcription factor activity (AP-1) compared to those who were low in SES early in life but experienced low maternal warmth. To the extent that such effects are causal, they suggest the possibility that the detrimental immunologic effects of low early-life SES environments may be partly diminished through supportive family climates.

Inflammatory Biomarkers and Fatigue during Radiation Therapy for Breast and Prostate Cancer

Purpose: Biomarkers of radiation-induced behavioral symptoms, such as fatigue, have not been identified. Studies linking inflammatory processes to fatigue in cancer survivors led us to test the hypothesis that activation of the proinflammatory cytokine network is associated with fatigue symptoms during radiation therapy for breast and prostate cancer. Experimental Design: Individuals with early-stage breast (n = 28) and prostate cancer (n= 20) completed questionnaires and provided blood samples for determination of serum levels of interleukin 1β (IL-1β) and IL-6 at assessments conducted before, during, and after a course of radiation therapy. Serum markers of proinflammatory cytokine activity, including IL-1 receptor antagonist and C-reactive protein, were examined in a subset of participants. Random coefficient models were used to evaluate the association between changes in cytokine levels and fatigue. Results: As expected, there was a significant increase in fatigue during radiation treatment. Changes in serum levels of inflammatory markers C-reactive protein and IL-1 receptor antagonist were positively associated with increases in fatigue symptoms (Ps < 0.05), although serum levels of IL-1β and IL-6 were not associated with fatigue. These effects remained significant (Ps < 0.05) in analyses controlling for potential biobehavioral confounding factors, including age, body mass index, hormone therapy, depression, and sleep disturbance. Conclusions: Results suggest that activation of the proinflammatory cytokine network and associated increases in downstream biomarkers of proinflammatory cytokine activity are associated with fatigue during radiation therapy for breast and prostate cancer.(Clin Cancer Res 2009;15(17):5534–40)

Social identity and physical health: accelerated HIV progression in rejection-sensitive gay men.

Research linking sensitivity to others and their evaluation of the self to alterations in physiologic function led the authors to examine whether HIV infection might progress more rapidly in gay men who are particularly sensitive to social rejection. Analyses of data from a 9-year prospective study of 72 initially healthy HIV-positive gay men indicated that rejection-sensitive individuals experienced a significant acceleration in times to a critically low CD4 T lymphocyte level, times to AIDS diagnosis, and times to HIV-related mortality (despite control for a variety of potential biobehavioral confounders). Accelerated HIV progression was not observed in rejection-sensitive gay men who concealed their homosexual identity, suggesting that concealment may protect such individuals from negative health effects. Data distinguishing rejection sensitivity from other health-relevant psychosocial characteristics are presented, and possible links to HIV pathophysiology are described.