Exploring the relationship between DNA methylation age measures and psychoneurological symptoms in women with early-stage breast cancer.

PURPOSE: The epigenetic clock has been acknowledged as an indicator for molecular aging, but few studies have examined possible associations of DNA methylation (DNAm) age or age acceleration (AA) with symptom burden in individuals who are treated for cancer. This study explored the association of DNAm age or AA with psychoneurological (PN) symptoms, including cognitive impairment, fatigue, sleep disturbances, pain, and depressive symptoms, in breast cancer survivors over a 2-year period. METHODS: We measured PN symptoms using reliable instruments and DNAm levels by Infinium HumanMethylation450K BeadChip (N = 72). DNAm age was calculated by the Horvath, Grim, and Hannum-based intrinsic and extrinsic age estimations. AA was defined by the residual regressing estimated epigenetic age on chronological age. Mixed regression models were fitted for AA and changes in AA to study the association over time. Separate linear regression models and a mixed-effects model were fitted for AA at each time point. RESULTS: Horvath-AA, Grim-AA, and extrinsic epigenetic AA were significantly changed over time, while intrinsic epigenetic AA did not exhibit any temporal changes. Increased AA was associated with greater anxiety and fatigue, as well as worse cognitive memory, adjusting for race, BMI, income, chemotherapy, radiation therapy, and chronological age. Increased DNAm age was associated with greater anxiety over 2 years. CONCLUSION: Our findings suggest DNAm age and AA may be associated with PN symptoms over the course of cancer treatment and survivorship. Some PN symptoms may be amenable to preventive interventions targeted to epigenetic clocks that influence aging-associated processes.

A feasibility study on yoga's mechanism of action for chronic low back pain: psychological and neurophysiological changes, including global gene expression and DNA methylation, following a yoga intervention for chronic low back pain.

INTRODUCTION: Yoga has been shown to reduce pain and improve function in populations with chronic low back pain (cLBP), yet the underlying molecular mechanisms remain elusive. This study examined the feasibility and acceptability of a yoga research protocol, including recruitment, retention, and data collection, and investigated the preliminary effects of yoga on psychological and neurophysiological functions, including gene expression and DNA methylation profiles, in participants with cLBP. METHODS: A one-arm trial was conducted with 11 participants with cLBP who enrolled in a 12-week yoga intervention. Data on subjective pain characteristics, quantitative sensory testing, and blood for analysis of differentially expressed genes and CpG methylation was collected prior to the start of the intervention and at study completion. RESULTS: Based on pre-determined feasibility and acceptability criteria, the yoga intervention was found to be feasible and highly acceptable to participants. There was a reduction in pain severity, interference, and mechanical pain sensitivity post-yoga and an increase in emotion regulation and self-efficacy. No adverse reactions were reported. Differential expression analysis demonstrated that the yoga intervention induced increased expression of antisense genes, some of which serve as antisense to known pain genes. In addition, there were 33 differentially hypomethylated positions after yoga (log2 fold change ≥ 1), with enrichment of genes involved in NIK/NF-kB signaling, a major pathway that modulates immune function and inflammation. DISCUSSION/CONCLUSIONS: The study supports the feasibility and acceptability of the proposed protocol to test a specific mechanism of action for yoga in individuals with cLBP. These results also support the notion that yoga may operate through our identified psychological and neurophysiologic pathways to influence reduced pain severity and interference.

Longitudinal Analysis of Sleep Disturbance in Breast Cancer Survivors.

BACKGROUND: Breast cancer survivors (BCS) often report poor sleep quality and wakefulness throughout the night as the greatest challenges experienced during and posttreatment. OBJECTIVES: This study aimed to elucidate characteristics of sleep disturbances and determine potential predictors that affect sleep disturbances in BCS for 2 years postchemotherapy. METHODS: This is a secondary analysis of data from the EPIGEN study, which longitudinally examined sociodemographic and cancer-related factors, lifestyle, symptom characteristics, and epigenetic factors at baseline prior to chemotherapy (T1), the midpoint (T2), 6-month (T3), 1-year (T4), and 2-year (T5) time points postchemotherapy. Temporal lifestyle changes, symptom characteristics, and epigenetic factors were explored using linear mixed-effects models with a random intercept. A linear regression model was fitted to identify significant predictors of sleep disturbances at each time point. RESULTS: In 74 BCS with an average age of 51 years and 70% non-Hispanic White, BCS experienced severe sleep disturbances at T2, which gradually improved over time. Significant temporal changes in midsleep awakenings, early awakenings, and fatigue at work were observed, with disturbances being elevated at T2. Anxiety (T1, T2, and T4), fatigue (T3 and T4), and perceived stress (T3) were significant predictors after adjusting for radiation therapy, surgery, and adjuvant endocrine therapy. DISCUSSION: This study highlights that predictors of sleep disturbances change over time, with anxiety being a factor earlier in the treatment trajectory (prechemotherapy) and continuing over time with fatigue and perceived stress being involved later in the treatment trajectory. Our results indicate that symptom management strategies to address sleep disturbances should be tailored to the temporal factors that may change in severity during active treatment and early survivorship period. Findings gained from this study on sleep disturbance patterns and the potential risk factors can be incorporated into clinical practice in planning education and developing interventions.

Genetic Variation Associated With Depressive Symptoms in Breast Cancer Patients: A Systematic Review.

BACKGROUND: Depressive symptoms are highly prevalent in breast cancer patients. These symptoms can contribute to lower treatment adherence, increased healthcare charges, and higher mortality rates. Growing evidence suggests that genetic variations may be associated with depressive symptom susceptibility. OBJECTIVE: To comprehensively review current findings on the association of genetic variations with depressive symptoms in breast cancer patients. METHODS: A literature search was conducted using keywords such as gene variation, single-nucleotide polymorphism, depression/depressive symptoms, and breast cancer. Four hundred articles were retrieved from PubMed, Web of Science, CINAHL, and PsycINFO, yielding 9 full-text, data-based articles. The study quality was assessed using the STrengthening the REporting of Genetic Association studies guideline. RESULTS: Genetic polymorphisms in brain-derived neurotrophic factor (BDNF), interferon γ receptor 1 (IFNGR1), interleukin-6 (IL-6), tumor necrosis factor α (TNFA), and IL-1B were found to be associated with depressive symptoms among breast cancer patients. The role of serotonin transporter gene linked promotor region (5-HTTLPR) functional polymorphisms on depressive symptoms was inconclusive. The overall quality of reporting results and methods was medium. CONCLUSIONS: This is the first review of genetic variations related to differences in levels of depressive symptoms among breast cancer patients. Genetic polymorphisms in inflammatory, neuronal system, and signal transduction pathways can influence the susceptibility. However, more research regarding this topic is needed to further clarify genetic risk factors. IMPLICATIONS FOR PRACTICE: Healthcare providers may determine patients at higher risk of developing depression and symptom outcomes if genetic biomarkers with good sensitivity/specificity are provided. This knowledge can potentially help the development of personalized treatment and decision making for those patients.

Metabolomics: Impact of Comorbidities and Inflammation on Sickness Behaviors for Individuals with Chronic Wounds.

Significance: Approximately 6.5 million people in the United States suffer from chronic wounds. The chronic wound population is typically older and is characterized by a number of comorbidities associated with inflammation. In addition to experiencing wound-related pain, individuals with chronic wounds commonly experience multiple concurrent psychoneurological symptoms such as fatigue and depression, which delay wound healing. However, these distressing symptoms have been relatively overlooked in this population, although their adverse effects on morbidity are well established in other chronic disease populations. Recent Advances: Inflammation is involved in multiple pathways, which activate brain endothelial and innate immune cells that release proinflammatory cytokines, which produce multiple symptoms known as sickness behaviors. Inflammation-based activation of the kynurenine (KYN) pathway and its metabolites is a mechanism associated with chronic illnesses. Critical Issues: Although putative humoral and neuronal routes have been identified, the specific metabolic variations involved in sickness behaviors in chronic wound patients remain unclear. To improve health outcomes in the chronic wound population, clinicians need to have better understanding of the mechanisms underlying sickness behaviors to provide appropriate treatments. Future Directions: This article presents a synthesis of studies investigating associations between inflammation, metabolic pathways, and sickness behaviors in multiple chronic diseases. The presentation of a theoretical framework proposes a mechanism underlying sickness behaviors in the chronic wound population. By mediating the immune system response, dysregulated metabolites in the KYN pathway may play an important role in sickness behaviors in chronic inflammatory conditions. This framework may guide researchers in developing new treatments to reduce the disease burden in the chronic wound population.

Relationships Among Fatigue, Anxiety, Depression, and Pain and Health-Promoting Lifestyle Behaviors in Women With Early-Stage Breast Cancer.

BACKGROUND: With a nearly 89% 5-year survival rate for women with early-stage breast cancer, symptoms are a priority. Healthy lifestyle behaviors may be temporally associated with symptoms; however, evidence is lacking. OBJECTIVE: This research examined temporal relationships among healthy lifestyle behaviors and symptoms in women diagnosed with breast cancer receiving chemotherapy. METHODS: This research was part of a study (R01NR012667) approved by the institutional review board. Women (n = 76) providing written informed consent participated in this longitudinal study examining health-promoting lifestyle behaviors and symptoms (fatigue, anxiety, depression, and pain). Participants completed well-validated self-report questionnaires primarily at a clinic visit. Statistical methods included descriptive statistics, linear mixed-effects models, and pairwise comparisons using SAS 9.4; α was set at .05. RESULTS: Lowest healthy lifestyle behavior scores for physical activity and highest scores for spiritual growth were reported. Significant changes in physical activity and stress management were noted. Fatigued patients had lower physical activity and nutrition scores than did patients without fatigue. Patients with anxiety had lower spiritual growth and interpersonal relation scores than did patients without anxiety. Relationships demonstrated temporal differences. CONCLUSIONS: Breast cancer survivors did not routinely engage in healthy lifestyle behaviors. Significant temporal changes in healthy lifestyle behaviors and symptoms and significant associations among healthy lifestyle behaviors, symptoms, and demographic and clinical factors were noted in this study. IMPLICATIONS FOR PRACTICE: Knowing the temporal relationships among these variables provides insight that could be useful for nurses so they can encourage healthy lifestyle behaviors to mitigate symptoms throughout the cancer trajectory.

Differential DNA methylation following chemotherapy for breast cancer is associated with lack of memory improvement at one year.

The biological basis underlying cognitive dysfunction in women with early-stage breast cancer (BC) remains unclear, but could reflect gene expression changes that arise from the acquisition and long-term retention of soma-wide alterations in DNA methylation in response to chemotherapy. In this longitudinal study, we identified differences in peripheral methylation patterns present in women prior to treatment (T1) and 1 year after receiving chemotherapy (T4) and evaluated relationships among the differential methylation (DM) ratios with changes in cognitive function. A total of 58 paired (T1 and T4) blood specimens were evaluated. Methylation values were determined for DNA isolated from whole blood using a genome-wide array . Cognitive function was measured using the validated, computerized CNS Vital Signs platform. Relationships between methylation patterns and cognitive domain scores were compared using a stepwise linear regression analysis, with demographic variables as covariates. The symptom comparison analysis was restricted to 2,199 CpG positions showing significant methylation ratio changes between T1 and T4. The positions with DM were enriched for genes involved in the modulation of cytokine concentrations. Significant DM ratios were associated with memory domain (56 CpGs). Eight of the ten largest DM ratio changes associated with lack of memory improvement were localized to genes involved in either neural function (ECE2, PPFIBP2) or signalling processes (USP6NL, RIPOR2, KLF5, UBE2V1, DGKA, RPS6KA1). These results suggest that epigenetic changes acquired and retained for at least one year in non-tumour cells following chemotherapy may be associated with a lack of memory improvement following treatment in BC survivors.

Genetic Variants Associated with Cancer Pain and Response to Opioid Analgesics: Implications for Precision Pain Management.

OBJECTIVE: To review the current knowledge on the association of genetic variants with cancer pain. DATA SOURCES: Data-based publications and review articles retrieved from PubMed, CINAHL, and Web of Science, as well as an additional search in Google Scholar. CONCLUSION: Genetic variability can influence differential pain perception and response to opioids in cancer patients, which will have implications in the optimal personalized treatment of cancer pain. More studies are warranted to replicate findings. IMPLICATIONS FOR NURSING PRACTICE: Nurses are poised to educate patients on biomarker testing and interpretation and to use precision pain management strategies based on this information.

Relationship of fatigue with cognitive performance in women with early-stage breast cancer over 2 years.

OBJECTIVE: Fatigue and cognitive dysfunction are major concerns for women with early-stage breast cancer during treatment and into survivorship. However, interrelationships of these phenomena and their temporal patterns over time are not well documented, thus limiting the strategies for symptom management interventions. In this study, changes in fatigue across treatment phases and the relationship among fatigue severity and its functional impact with objective cognitive performance were examined. METHODS: Participants (N = 75) were assessed at five time points beginning prior to chemotherapy to 24 months after initial chemotherapy. Fatigue severity and impact were measured on the Brief Fatigue Inventory. Central nervous system (CNS) Vital Signs was used to measure performance based cognitive testing. Temporal changes in fatigue were examined, as well as the relationship between fatigue and cognitive performance, at each time point using linear mixed effect models. RESULTS: Severity of fatigue varied as a function of phase of treatment. Fatigue severity and its functional impact were moderate at baseline, increased significantly during chemotherapy, and returned to near baseline levels by 2 years. At each time point, fatigue severity and impact were significantly associated with diminished processing speed and complex attention performance. CONCLUSIONS: A strong association between fatigue and objective cognitive performance suggests that they are likely functionally related. That cognitive deficits were evident at baseline, whereas fatigue was more chemotherapy dependent, implicates that two symptoms share some common bases but may differ in underlying mechanisms and severity over time. This knowledge provides a basis for introducing strategies for tailored symptom management that vary over time.

Systematic review of genetic polymorphisms associated with psychoneurological symptoms in breast cancer survivors.

PURPOSE: Psychoneurological (PN) symptoms, such as anxiety, cognitive impairment, depression, fatigue, sleep disturbances, and pain, are highly prevalent in breast cancer patients undergoing cancer treatment. Emerging evidence suggests that genetic polymorphisms may contribute to differential symptom susceptibility. We aimed to systematically review associations between genetic polymorphisms and PN symptoms during or after cancer treatment for early-stage breast cancer. METHODS: Twenty-six eligible articles published until October 2017 were identified in PubMed, PsycINFO, Web of Science, and additional records. Information on study characteristics, genetic polymorphisms, and PN symptoms was extracted. Study quality was evaluated by the STrengthening the REporting of Genetic Association (STREGA) guideline. Genes included in the analysis were categorized by biological pathways based on the Reactome database. RESULTS: A total of 54 single nucleotide polymorphisms and haplotypes that are significantly associated with PN symptoms were identified; half of them were associated with increased severity of PN symptoms, while the other half contributed to the decrease of PN symptoms. Pain has the known highest number of associated genetic polymorphisms reported, followed by fatigue, cognitive impairment, depressive symptoms, sleep disturbances, and anxiety. The majority of genetic polymorphisms were involved in immune system and neuronal system pathways. Most studies were unsuccessful in meeting the STREGA guideline, which requires transparent reporting of methods and results. CONCLUSIONS: This review provides comprehensive evidence of genetic polymorphisms underlying PN symptoms, which may pave the way for the development of personalized therapeutics targeting these symptoms. More well-designed genome-wide association studies are required to validate and replicate these findings.

Interventions for the Treatment of Aromatase Inhibitor-Associated Arthralgia in Breast Cancer Survivors: A Systematic Review and Meta-analysis.

BACKGROUND: Aromatase inhibitors (AIs) have been established as successful adjuvant therapy for breast cancer survivors. Unfortunately, nearly half of women taking AIs report joint pain, AI-associated arthralgia (AIA). Aromatase inhibitor-associated arthralgia often results in noncompliance, which could lead to cancer recurrence. OBJECTIVE: The purpose of this study was to identify current pain management of AIA and to evaluate the study quality and effects of interventions. METHODS: Nineteen articles published from 2000 to August 2015 were identified using PubMed, CINAHL, PsycINFO, Web of Science, and additional records. Study quality was evaluated by the Quality Assessment Tool for Quantitative Studies. Meta-analysis was used to obtain effect sizes of interventions on pain and subgroups. RESULTS: Five types of interventions emerged: pharmacological approaches, acupuncture, nutritional supplementation, relaxation techniques, and physical exercise. Six studies were strong, 8 were moderate, and 5 were weak in quality. The overall effect size of the interventions on pain was large; pharmacological approaches, acupuncture, and relaxation techniques showed moderate to large effects on pain, whereas nutritional supplementation and physical exercise had no significant effects on it. CONCLUSION: The evidence was based on a body of research with moderate study quality. Although the overall effect of interventions is large, further investigation into the influence of nutrition and physical exercise is needed to better discern their potential for pain management. IMPLICATION FOR PRACTICE: Oncology nurses may be able to implement such validated interventions as pain management modalities to mitigate the symptoms so that breast cancer survivors remain compliant with AIA therapy.

Racial and ethnic differences in experimental pain sensitivity: systematic review and meta-analysis.

Our objective was to describe the racial and ethnic differences in experimental pain sensitivity. Four databases (PubMed, EMBASE, the Cochrane Central Register of Controlled Trials, and PsycINFO) were searched for studies examining racial/ethnic differences in experimental pain sensitivity. Thermal-heat, cold-pressor, pressure, ischemic, mechanical cutaneous, electrical, and chemical experimental pain modalities were assessed. Risk of bias was assessed using the Agency for Healthcare Research and Quality guideline. Meta-analysis was used to calculate standardized mean differences (SMDs) by pain sensitivity measures. Studies comparing African Americans (AAs) and non-Hispanic whites (NHWs) were included for meta-analyses because of high heterogeneity in other racial/ethnic group comparisons. Statistical heterogeneity was assessed by subgroup analyses by sex, sample size, sample characteristics, and pain modalities. A total of 41 studies met the review criteria. Overall, AAs, Asians, and Hispanics had higher pain sensitivity compared with NHWs, particularly lower pain tolerance, higher pain ratings, and greater temporal summation of pain. Meta-analyses revealed that AAs had lower pain tolerance (SMD: -0.90, 95% confidence intervals [CIs]: -1.10 to -0.70) and higher pain ratings (SMD: 0.50, 95% CI: 0.30-0.69) but no significant differences in pain threshold (SMD: -0.06, 95% CI: -0.23 to 0.10) compared with NHWs. Estimates did not vary by pain modalities, nor by other demographic factors; however, SMDs were significantly different based on the sample size. Racial/ethnic differences in experimental pain sensitivity were more pronounced with suprathreshold than with threshold stimuli, which is important in clinical pain treatment. Additional studies examining mechanisms to explain such differences in pain tolerance and pain ratings are needed.

Fatigue in Irritable Bowel Syndrome: A Systematic Review and Meta-analysis of Pooled Frequency and Severity of Fatigue.

PURPOSE: Fatigue is the third most common "extraintestinal" complaint of patients with irritable bowel syndrome (IBS), but it is still poorly understood. This study aimed to review characteristics of IBS-associated fatigue and to examine pooled frequency, severity of fatigue, and correlations of related factors with fatigue in IBS via meta-analyses. METHODS: Publications were searched in eight databases from 1995 to 2014. Random effects meta-analyses were applied with standard error, weighted effect size, and correlation-based measure of effect size. RESULTS: Twenty-four studies were included in systematic review. Seventeen studies were used for meta-analyses (2 studies were excluded in the frequency of fatigue analysis due to data unavailability). Using "tiredness" to define fatigue, and Fatigue Impact Scale to assess fatigue were the most frequently used across the studies. Gastrointestinal symptoms, psychological distress, and health-related quality of life were the most common correlates with fatigue. The pooled frequency of fatigue was 54.2% [95% confidence interval (38.5, 69.4)]. Metaregression on the frequency of fatigue showed positive and significant relations with tertiary care settings, female sex, and younger age. There was a negatively moderate relationship between the severity of fatigue and health-related quality of life score (correlation-based measure of effect size: -.378). CONCLUSIONS: Fatigue is prevalent among patients with IBS and commonly co-occurs with other symptoms. This is the first study to fully examine fatigue in IBS, which shed light on the comprehensive management of fatigue in this patient group. Future research is warranted to further explore fatigue-related factors and underlying mechanisms of fatigue in IBS.

Evaluation of dynamic weight bearing for measuring nonevoked inflammatory hyperalgesia in mice.

BACKGROUND: Animal models in pain research have suggested that inclusion of both evoked and nonevoked behavioral measures is needed to better reflect the human pain experience. Individuals with chronic pain are known to experience spontaneous pain, in addition to pain after exposure to an external stimulus. Recently, the dynamic weight bearing (DWB) apparatus was developed to assess for nonevoked hyperalgesia by capturing weight bearing and surface distribution in the paws of mice after acute inflammation. OBJECTIVES: The aim of this study was to evaluate the DWB test as a measure of nonevoked hyperalgesia. METHODS: The experimental group received an intraplantar injection in the left hind paw of the inflammatory agent--complete Freund's adjuvant (CFA)--whereas the vehicle control group received a saline injection and the naive control group had no treatment. Calipers and a plethysmometer were used to verify inflammation and the hot-plate test was used as a measure for stimulus-evoked hyperalgesia. Data were collected at baseline; 3 hours; and 1, 3, and 7 days after injection. RESULTS: Mice injected with CFA showed a statistically significant higher mean paw thickness and volume displacement compared with the vehicle and naive control groups. In the hot-plate testing, CFA-treated mice showed lower response temperature at 7 days compared with the other groups. On the DWB test, CFA-treated mice showed a reduction in the ipsilateral paw load and surface area compared with the contralateral paw load at Days 1, 3, and 7. DISCUSSION: Mice with inflammation showed alterations in weight bearing as well as increased thermal hyperalgesia in comparison with control groups. These findings support the use of the DWB test as a tool for measuring nonevoked inflammatory hyperalgesia in a mouse model.

[Effect of anorexia and neuropathic pain induced by cisplatin on hindlimb muscles of rat].

PURPOSE: The purpose of this study was to examine the effect of anorexia and neuropathic pain induced by cisplatin on hindlimb muscles of rats. METHODS: Adult male Sprague-Dawley rats were divided into two groups, a cisplatin-treated group (n=10) and a control group (n=10). In the cisplatin-treated group, cisplatin at a dose of 2 mg/kg was injected intraperitoneally two times a week up to a cumulative dose of 20 mg/kg over 5 weeks, and in the control group saline (0.9% NaCl) was injected intraperitoneally at the same dose and duration as the cisplatin-treated group. At 34 days all rats were anesthetized, after which the soleus and plantaris muscles were dissected. Withdrawal threshold, body weight, food intake, activity, muscle weight, Type I and II fiber cross-sectional areas and myofibrillar protein content of the dissected muscles were determined. RESULTS: Compared with the control group, the cisplatin-treated group showed significant decreases (p<.05) in withdrawal threshold, activity, food intake, body weight, Type I and II fiber cross-sectional areas, myofibrillar protein content and weight of the soleus and plantaris muscles. CONCLUSION: Muscular atrophy in hindlimb occurs due to anorexia and neuropathic pain induced by the cisplatin treatment.