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Background: Although some studies show that there could be a genetic predisposition to develop Multiple Sclerosis (MS), attempts to find genetic signatures related to MS diagnosis and development are extremely rare., Method: We carried out a retrospective analysis of two different microarray datasets, using machine learning techniques to understand the defective pathways involved in this disease. We have modeled two data sets that are publicly accessible. The first was used to establish the list of most discriminatory genes; whereas, the second one was utilized for validation purposes., Results: The analysis provided a list of high discriminatory genes with predictive cross-validation accuracy higher than 95%, both in learning and in blind validation. The results were confirmed via the holdout sampler. The most discriminatory genes were related to the production of Hemoglobin. The biological processes involved were related to T-cell Receptor Signaling and co-stimulation, Interferon-Gamma Signaling and Antigen Processing and Presentation. Drug repositioning via CMAP methodologies highlighted the importance of Trichostatin A and other HDAC inhibitors., Conclusions: The defective pathways suggest viral or bacterial infections as plausible mechanisms involved in MS development. The pathway analysis also confirmed coincidences with Epstein-Barr virus, Influenza A, Toxoplasmosis, Tuberculosis and Staphylococcus Aureus infections. Th17 Cell differentiation, and CD28 co-stimulation seemed to be crucial in the development of this disease. Furthermore, the additional knowledge provided by this analysis helps to identify new therapeutic targets., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Purpose: To reduce chemotherapy-induced neuropathy (CIN)-a significant challenge among cancer patients following chemotherapy-we explored the effects of auricular point acupressure (APA), which involves needleless, acupuncture-like stimulation on specific ear points., Design/method: This pilot study examined the effects of a 4-week APA intervention in the management of CIN. Descriptive analysis was used to examine the changes in study outcomes., Results: Fifteen participants were enrolled. Two participants dropped out because they developed new medical conditions. Thirteen participants completed the study (87% retention rate). Study participants had more severe symptoms in their lower extremities (i.e., toes, feet, soles) than in their upper extremities (i.e., fingers, wrists, elbows). After the 4-week APA intervention, the mean percentage change scores ranged from 38% (tingling) to 49% (numbness); compared to pre-intervention, the therapeutic effects of APA were sustained at the 1-month follow-up. Function in both upper and lower extremities improved after the APA intervention (≥28%) and continued to improve at the 1-month follow-up (≥36%)., Conclusions: Preliminary results from this small sample provide initial evidence of the effectiveness of APA on CIN. Future studies should confirm these results using a larger sample, a comparative sham control, and an examination of the underlying physiological mechanisms of the anti-CIN effects of APA., Clinical Implications: APA may provide an inexpensive and effective complementary approach for the self-management of CIN. Once the seeds have been taped to the patient's ear by the provider, patients are empowered to self-manage their CIN in their own environment., (Copyright © 2019 American Society for Pain Management Nursing. Published by Elsevier Inc. All rights reserved.)

Purpose: To manage chemotherapy-induced neuropathy (CIN), this paper explores reliable and valid objectives measures to evaluate the treatment effects of auricular point acupressure (APA)., Design/method: This study was a repeated-measures one-group design. Participants received four weeks of APA to manage their CIN. The laboratory-assessed and objective outcomes included quantitative sensory testing, grip and pinch strength, and inflammatory biomarkers. Wilcoxon matched pairs signed-rank tests were conducted to determine change scores of outcomes at pre- vs. post- and pre- vs. 1-month follow-up. Spearman's rho correlation coefficient was used to examine the linear association of score changes of all objective study outcomes., Results: Comparing pre-and-post APA, (1) the mean score of the monofilament for all lower extremity sites tested decreased after APA, indicating sensory improvement; (2) the suprathreshold pinprick stimuli mean scores on the upper extremities increased, except the scores from the index finger and thumb; (3) the pain tolerance of thumb and trapezius areas increased; (4) decreasing IL1β (p = .05), IFNγ (p = .02), IL-2 (p = .03), IL-6 (p = .05), IL-10 (p = .05), and IP10/CXCL10 (p = .04) were observed pre-post APA. Conditional pain modulation was significantly (p< .05) associated with pain intensity (r = 0.55), tingling (r = 0.59); and IL1β concentration (r = 0.53) pre-post APA. The sustained effects of 4-week APA were observed at the 1-month follow-up., Conclusions: Our study findings demonstrated the promising effectiveness of APA in the management of CIN, and these treatment effects can be assessed using reliable and valid objective measures., Clinical Implications: If the efficacy of APA to manage CIN is confirmed in a larger sample, APA has the potential to be a scalable treatment for CIN because it is a reproducible, standardized, and easy-to-perform intervention., (Copyright © 2019 American Society for Pain Management Nursing. All rights reserved.)

Background: Cancer-related fatigue (CRF) is a debilitating symptom frequently reported by patients during and after treatment for cancer. CRF is a multidimensional experience and is often solely assessed by self-report measures. The goal of the study is to examine the physical and cognitive aspects of self-reported CRF using a cognitive function test and a physical fatigue index in order to provide objective measures that can characterize the CRF phenotype., Methods: A total of 59 subjects with nonmetastatic prostate cancer receiving external beam radiation therapy were included in the study. Fatigue was measured using the Functional Assessment of Cancer Therapy-Fatigue (FACT-F) questionnaire. Cognitive characteristics of CRF was measured using the Stroop Color-Word Interference computerized test and the motor aspect of fatigue was measured using the static fatigue test using a handgrip dynamometer., Findings: Functional Assessment of Cancer Therapy-Fatigue scores significantly correlated with the Stroop Interference score, but not performance accuracy in all test conditions. Fatigued subjects exhibited a more rapid decline to 50% of maximal strength and increased static fatigue index in the handgrip test, whereas maximal grip strength was not affected., Conclusions: The results suggest that CRF exhibits both cognitive and physical characteristics. Subjective fatigue was associated with increased time required to overcome cognitive interference, but not cognitive performance accuracy. Fatigued patients exhibited decreased physical endurance and the ability to sustain maximal strength over time. These objective measures may serve as valuable tools for clinicians to detect cognitive and physical impairment associated with CRF., (Published 2019. This article is a U.S. Government work and is in the public domain in the USA. Cancer Medicine published by John Wiley & Sons Ltd.)

Purpose: Evidence has shown that cancer-related fatigue (CRF) may be a treatment-limiting symptom and often impairs health-related quality of life. Accurate assessment of the multidimensional nature of CRF could help drive interventions to mitigate this debilitating symptom. Currently, there are no clinical tools to effectively and efficiently assess the multidimensionality of CRF. The purpose of this paper is to introduce a CRF-specific short form that can assess the multidimensional nature of CRF for use in the clinical setting., Methods: The CRF-specific short form was developed using the 95-item PROMIS® fatigue bank. Bi-factor analysis was used to evaluate dimensionality of the alternative model using fatigue for the general factor and physical, cognitive, affective, global, and motivational for the local factors. After unidimensionality was confirmed (loading factor > 0.3), one item from each local factor was selected using discrimination power for inclusion in the CRF-specific short form., Results: The Research Assessment and Clinical Tool-Fatigue (ReACT-F) was created from the 95-item PROMIS fatigue bank using established item parameters. The ReACT-F assesses five common dimensions of CRF as well as perceived burden of the fatigue dimensions., Conclusions: The ReACT-F is a CRF-specific self-report short form that addresses the need for a brief, clinically useful tool to quickly assess the multidimensional nature of CRF. We anticipate that the ReACT-F can be completed in the clinical setting in approximately 3 minutes, providing clinicians with meaningful data to drive personalized interventions. Further validation of the ReACT-F is highly encouraged.

Objective: To examine the relationship of the symptoms of diarrhea and fatigue by testing a model that included multiple dimensions of the cancer related-symptom experience., Methods: A secondary data analysis was conducted on data from the self-reports of 102 cancer patients co experiencing diarrhea and fatigue during treatment at a comprehensive cancer center in the Southeastern United States. Structural equational modeling was employed to examine the relationship between the 2variables. Fatigue and diarrhea were assessed using items from the Cancer Symptom Scale., Results: The structural model results showed that (a) the model fit was adequate (b) diarrhea explained 7% of the variance in fatigue, and (c) the structural or path coefficient between diarrhea and fatigue was significant (0.267; p<0.05). Diarrhea had the strongest effect on fatigue interference (0.251)., Conclusion: Diarrhea is a potential contributing factor to the symptom of fatigue and a potential target for interventions to prevent and ameliorate fatigue.

Background: Fatigue and depression are closely associated. The purpose of this secondary analysis was to understand the relationships between depression and improvements in specific depression domains on the anti-fatigue effects of ketamine, which we previously reported., Methods: This secondary analysis re-evaluated data collected longitudinally from 39 patients with treatment-resistant Major Depressive Disorder (MDD) enrolled in a double-blind, randomized, placebo-controlled, crossover trial using a single intravenous infusion of ketamine hydrochloride (0.5 mg/kg over 40 minutes) or placebo. A mediation model assessed the effect of depression on the anti-fatigue effects of a single dose of intravenous ketamine versus placebo at Day 1 post-infusion. Fatigue was measured using the National Institutes of Health-Brief Fatigue Inventory (NIH-BFI), and depression was assessed by the Montgomery-Ǻsberg Depression Rating Scale (MADRS)., Results: Compared to placebo, ketamine significantly improved fatigue (p = .0003) as measured by the NIH-BFI, but the anti-fatigue effects of ketamine disappeared (p = .47) when controlling for depression as measured by MADRS total score. In this study sample, the anti-fatigue effects of ketamine were mostly accounted for by the changes in amotivation and depressed mood scores., Conclusions: In this study, ketamine did not have a unique effect on fatigue outside of its general antidepressant effects in patients with treatment-resistant depression. Specifically, the anti-fatigue effects of ketamine observed in this study seem to be explained by the effects of ketamine on two symptom domains of depression: amotivation and depressed mood. The study findings suggest that the anti-fatigue effects of ketamine should be assessed by fatigue-specific measures other than the NIH-BFI or future studies should enroll fatigued patients without depression., (Published by Elsevier B.V.)

Purpose: To describe the collaborative framework used by National Institute of Nursing Research (NINR) investigators to advance symptom science and to provide a research exemplar., Model: The National Institutes of Health (NIH) Symptom Science Model (SSM) was developed to guide symptom science researchers to understand the molecular underpinnings of symptoms using innovative "omics" approaches. The process begins with a review of the literature to understand the state of the science of the symptoms of interest and is followed by cross-sectional, case-controlled, or longitudinal studies to identify potential biological correlates of these symptoms. The final steps include validation of these potential symptom biomarkers using multidisciplinary, collaborative, preclinical experiments, and proof-of-concept clinical trials., Research Exemplar: Using the NIH SSM as a guide, the identification of biologic correlates of symptoms using omics and bioinformatic strategies depends on determining the distinct phenotype of the symptoms of interest. The identified biologic correlates of these symptoms are then validated for their functional relevance using in vitro and ex vivo experiments, or through proof-of-concept clinical trials. NINR investigators observed that activation of specific receptors in neural networks can trigger inflammation-related fatigue development and predispose patients to develop chronicity of symptoms. Specifically targeting these neural receptors can reduce symptom intensity., Conclusions: Through using the NIH SSM as a guide, NINR investigators quickly generate data and discoveries that significantly advance symptom science by simultaneously collaborating with multiple experts and core laboratories to identify more correlates and validate their functional relevance in order to further understand the biological underpinnings of the symptoms of interest., Clinical Relevance: The collaborative framework used by NINR investigators as guided by the NIH SSM identifies functionally relevant clinical markers that can explain the biological underpinnings of symptoms and can be targeted to optimize symptom management., (© 2018 Sigma Theta Tau International.)

Purpose: Cancer-related fatigue is one of the most debilitating side effects of cancer and cancer therapy. We aimed to investigate co-occurring symptoms associated with persistent fatigue in men receiving external beam radiation therapy (EBRT) for nonmetastatic prostate cancer., Methods: A sample of 47 men with prostate cancer scheduled to receive radiotherapy (RT) were followed at baseline and 1 year after RT. Clinical and demographic data were obtained from chart review. Symptom measurements included urinary dysfunction (American Urological Association symptoms score), fatigue (Functional Assessment of Cancer Therapy - Fatigue questionnaire), sleep disturbance (Patient-Reported Outcomes Measurement Information System - Sleep Disturbance form), pain (physical well-being domain pain item of the Functional Assessment of Cancer Therapy - General), and depressive symptoms (Hamilton Depression Rating Scale). Paired t tests, correlations, general linear models, and logistic regressions were used to determine associations between fatigue and other symptom scores., Results: At 1 year after RT, 34% of subjects continued to experience fatigue. Urinary dysfunction was the best clinical predictor of persistent fatigue. Pain and depressive symptoms further improved the predictive power of the model. A multivariate linear regression model containing all these three clinical variables (urinary dysfunction, pain, and depressive symptoms) explained 74% of total variance associated with persistent fatigue after RT., Conclusions: Persistent fatigue at 1 year after EBRT in prostate cancer survivors is likely related to a cluster of symptoms elicited by chronic inflammation. Therapies that target each of these symptoms will likely reduce fatigue in this patient population., (© 2019 S. Karger AG, Basel.)

Aim: To assess the validity of the translated Spanish Cancer Symptom Scale., Background: Instruments to facilitate comprehensive and objective assessments of the cancer symptom experience in underrepresented populations are essential., Methods: The Cancer Symptom Scale was translated into Spanish, and a back translation was conducted. During June 2016, a sample of 121 Hispanic Puerto Rican patients with any cancer diagnosis, all undergoing cancer treatments, completed four paper surveys. A subgroup of 15 patients agreed to complete the Spanish Cancer Symptom Scale a second time after a short delay of 1 to 2 hours. Construct validity and reliability (internal consistency via Cronbach alpha and test-retest reliability) was evaluated., Results: All the Intensity Items of the Spanish Cancer Symptom Scale correlated significantly with the matched items on the MD Anderson Symptom Inventory. In a subgroup of 77 participants, each Cancer Symptom Scale subscale total of scores correlated significantly with the total scores from the Functional Assessment of Cancer Therapy-General. Discriminant validity was demonstrated between those receiving chemotherapy and those from post treatment. The Spanish Cancer Symptom Scale internal consistency reliability was 0.98., Conclusion: The Spanish Cancer Symptom Scale has excellent evidence of validity and reliability for assessing cancer-therapy-related symptoms., (© 2018 John Wiley & Sons Australia, Ltd.)

Fatigue is a very common and costly symptom associated with various diseases and disorders. Nonetheless, understanding the pathobiology and developing of therapies for fatigue have been difficult, partly because of a lack of consensus on the measures to phenotype this behavior, both in clinical settings and in animal studies. Here, we describe a fatigue-like behavior induced in mice by abdominal irradiation and compare three different methods of measuring changes in physical activity over time: running wheels, video home cage monitoring, and telemetry. These methods collect data passively and continuously, requiring no disruption of animals' normal home cage behavior. In our experiments, all three methods reported a fatigue-like behavior, exhibited by a reduction in physical activity following abdominal irradiation. Video tracking showed the largest fatigue effect size (Cohen's D = 1.78) over four days of monitoring, and was the only method showing a significant decrease in activity during the light period. Telemetry and running wheels showed a similar effect size (D = 1.68 and 1.65, respectively), but running wheels showed different circadian patterns of physical activity. In addition, we conducted rotarod and inverted grid suspension tests, which suggested that fatigue-like behavior was not the result of gross motor abnormalities.

Aims and Objectives: To describe differences in fatigue severity in a sample of adult Puerto Rican patients during and postcancer treatments., Background: Hispanics, including Puerto Ricans, are an understudied population who are under-represented in clinical trials, especially in symptom research. Although symptom management is a clinical priority in oncology care, treatment-related differences in Puerto Rican cancer patients' report of fatigue severity have not been well described., Design/methods: A cross-sectional survey was conducted from data of self-report of 138 Puerto Rican patients during and postcancer treatments at two ambulatory facilities located in San Juan, Puerto Rico. Fatigue severity was assessed using the Fatigue subscale from the Functional Assessment of Cancer Therapy-Fatigue quality of life questionnaire Spanish version. Differences in fatigue severity across type of treatment (radiation therapy, chemotherapy, combined radiation chemotherapy and post-treatment) were evaluated using nonparametric (Kruskal-Wallis and Mann-Whitney test) statistical tests., Results: The majority of the participants had prostate (33%) and breast (32%) cancers and were receiving radiation therapy (43%) or chemotherapy (28%). The Kruskal-Wallis test showed that there was a statistically significant difference in fatigue scores between the different four treatment conditions, χ 2 (3) = 39.1, p = .001 with patients on combined radiation chemotherapy or chemotherapy alone experiencing more severe fatigue., Conclusions: Findings from the current study suggest that type of treatment is a key component of the symptom burden of fatigue among the Puerto Rican oncology population. Specially, patients receiving combined therapy or chemotherapy alone were at increased risk for experiencing severe fatigue, compared to radiation therapy and post-treatment patients., Relevance to Clinical Practice: With the worldwide increase in migration of Puerto Rican families, nurses need to recognise that type of treatment is a key component of the symptom burden of fatigue among the Puerto Rican population. The results of this study will improve understanding of treatment-related fatigue to identify therapeutic targets and improve quality of life of patients., (© 2017 John Wiley & Sons Ltd.)

The knowledge base of cancer-related symptoms is increasing; yet, limited attention has been given to provide evidence on differences in the perception of cancer symptoms between ethnic groups, especially in the Hispanic Puerto Rican (PR) population. To examine whether there are significant differences in the severity, distress, interference, and frequency of cancer symptoms between island Hispanic PR and mainland non-Hispanic whites. In this secondary data analysis, data from 109 Hispanic PR was matched by age, gender and cancer diagnosis with data from non-Hispanic whites. Cancer symptoms were assessed using the Cancer Symptom Scale (CSS). Mann-Whitney statistical test was used to evaluate pairwise differences between Hispanic PR and non-Hispanic whites on symptoms from the CSS. There were significant differences on some symptoms including PR reporting: (a) more intense itching, swelling, taste change, difficulty sleeping, bloating, depression, sadness, worry, and nervousness; (b) significantly greater distress about taste change, appetite, anxiety, depression, worry, and feeling nervous; (c) rash, anxiety, depression, sadness, and nervousness interfered the most with their daily lives; and, (d) that the frequency of occurrence of the symptoms of pain, itching, dizziness, taste change, anxiety, sadness, and nervousness was higher compared to non-Hispanic whites. PR cancer patients are at increased risk for experiencing greater severity of cancer symptoms compared to non-Hispanic whites. But because the Hispanic oncology population does not always report symptoms, risking under-assessment and under-management, this suggests there may be a greater need for symptoms surveillance for this population.

Background: Prostate cancer survivors commonly experience late-onset lower urinary tract symptoms following radiotherapy. We aimed to compare lower urinary tract symptoms in patients treated with stereotactic body radiotherapy (SBRT) to those treated with a combination of lower dose SBRT and supplemental intensity-modulated radiotherapy (SBRT + IMRT)., Methods: Subjects with localized prostate carcinoma scheduled to receive SBRT or a combination of SBRT and IMRT were enrolled and followed for up to 2 years after treatment completion. Participants treated with SBRT received 35-36.25 Gy in 5 fractions, while those treated with SBRT + IMRT received 19.5 Gy of SBRT in 3 fractions followed by 45-50.4 Gy of IMRT in 25-28 fractions. Urinary symptoms were measured using the American Urological Association (AUA) Symptom Score., Results: Two hundred patients received SBRT (52% intermediate risk, 37.5% low risk according to D'Amico classification) and 145 patients received SBRT + IMRT (61.4% high risk, 35.2% intermediate risk). Both groups experienced a transient spike in urinary symptoms 1 month after treatment. More severe late urinary flare (increase in AUA scores ≥ 5 points from baseline to 1 year after treatment completion and an AUA score ≥ 15 at 1 year after treatment) was experienced by patients who received SBRT compared to those treated with SBRT + IMRT., Conclusion: Participants who received SBRT and supplemental IMRT experienced less severe late urinary flare 1 year after treatment compared to those who received higher dose SBRT alone. This information can be used by clinicians to provide patients with anticipatory counseling to mitigate any psychological burden that comes with unanticipated late urinary toxicities.

Cancer-related fatigue (CRF) is a common burden in cancer patients and little is known about its underlying mechanism. The primary aim of this study was to identify gene signatures predictive of post-radiotherapy fatigue in prostate cancer patients. We employed Fisher Linear Discriminant Analysis (LDA) to identify predictive genes using whole genome microarray data from 36 men with prostate cancer. Ingenuity Pathway Analysis was used to determine functional networks of the predictive genes. Functional validation was performed using a T lymphocyte cell line, Jurkat E6.1. Cells were pretreated with metabotropic glutamate receptor 5 (mGluR5) agonist (DHPG), antagonist (MPEP), or control (PBS) for 20 min before irradiation at 8 Gy in a Mark-1 γ-irradiator. NF-κB activation was assessed using a NF-κB/Jurkat/GFP Transcriptional Reporter Cell Line. LDA achieved 83.3% accuracy in predicting post-radiotherapy fatigue. "Glutamate receptor signaling" was the most significant (p = 0.0002) pathway among the predictive genes. Functional validation using Jurkat cells revealed clustering of mGluR5 receptors as well as increased regulated on activation, normal T cell expressed and secreted (RANTES) production post irradiation in cells pretreated with DHPG, whereas inhibition of mGluR5 activity with MPEP decreased RANTES concentration after irradiation. DHPG pretreatment amplified irradiation-induced NF-κB activation suggesting a role of mGluR5 in modulating T cell activation after irradiation. These results suggest that mGluR5 signaling in T cells may play a key role in the development of chronic inflammation resulting in fatigue and contribute to individual differences in immune responses to radiation. Moreover, modulating mGluR5 provides a novel therapeutic option to treat CRF.

Fatigue is a common and debilitating condition that affects most cancer patients. To date, fatigue remains poorly characterized with no diagnostic test to objectively measure the severity of this condition. Here we describe an optimized method for assessing mitochondrial function of PBMCs collected from fatigued cancer patients. Using a compact extracellular flux system and sequential injection of respiratory inhibitors, we examined PBMC mitochondrial functional status by measuring basal mitochondrial respiration, spare respiratory capacity, and energy phenotype, which describes the preferred energy pathway to respond to stress. Fresh PBMCs are readily available in the clinical setting using standard phlebotomy. The entire assay described in this protocol can be completed in less than 4 hours without the involvement of complex biochemical techniques. Additionally, we describe a normalization method that is necessary for obtaining reproducible data. The simple procedure and normalization methods presented allow for repeated sample collection from the same patient and generation of reproducible data that can be compared between time points to evaluate potential treatment effects.

Objective: To examine the health related quality of life (HRQOL) experienced by 79 Puerto Rican adults during cancer treatments., Methods: This study used a descriptive, cross-sectional design. Participants completed a demographics form and the Functional Assessment of Cancer Therapy-General QOL questionnaire (FACT-G). Descriptive statistics were generated., Results: Participants were ages 28-78; most of the participants had breast (38.0%), prostate (14.0%) and cervical and ovarian cancers (10.1%) treated with chemotherapy (45.6%). The participants had a mean total score on the FACT-G of 75.2 (SD = 18.9). As a group, the functional well-being was the most affected (mean 17.2, SD 6.8), and the Social/Familial was the least affected (mean 20.7, SD 6.0)., Conclusion: Cancer is the leading cause of death in the island of Puerto Rico. Female Puerto Rican cancer patients in this study sample had increased risk for experiencing worse: overall HRQOL, physical well-being and emotional well-being compared to males. Given that the Hispanic oncology population does not always report symptoms, risking under-assessment and under management, this suggests there may be a greater need for HRQOL surveillance for this population.

Genetic factors that influence inflammation and energy production/expenditure in cells may affect patient outcomes following treatment with external beam radiation therapy (EBRT). Sestrins, stress-inducible genes with antioxidant properties, have recently been implicated in several behaviors including fatigue. This proof-of-concept study explored whether the sestrin family of genes ( SESN1, SESN2, and SESN3) were differentially expressed from baseline to the midpoint of EBRT in a sample of 26 Puerto Rican men with nonmetastatic prostate cancer. We also examined whether changes in expression of these genes were associated with changes in fatigue scores during EBRT., Method: Participants completed the 13-item Functional Assessment of Cancer Therapy-Fatigue subscale, Spanish version. Whole blood samples were collected at baseline and at the midpoint of EBRT. Gene expression data were analyzed using the limma package in the R (version R 2.14.0.) statistical software. Linear models and empirical Bayes moderation, adjusted for radiation fraction (total number of days of prescribed radiation treatment), were used to examine potential associations between changes in gene expression and change in fatigue scores., Results: Expression of SESN3 (adjusted p < .01, log fold change -0.649) was significantly downregulated during EBRT, whereas the expressions of SESN1 and SESN2 remained unchanged. After adjustment for radiation fraction, change in SESN3 expression was associated with change in fatigue during EBRT (false discovery rate <.01)., Conclusions: Downregulation of SESN3, a novel pharmacoactive stress response gene, was associated with fatigue intensification during EBRT. SESN3 may serve as an interventional target and a biomarker for the cellular and molecular events associated with EBRT-related fatigue.

Purpose: Cancer-related fatigue is a common complaint during cancer treatment and is often associated with cognitive impairment. This study examined cognitive deficits that were associated with fatigue symptoms during external-beam radiation therapy (EBRT) in men with localized prostate cancer., Methods: A total of 36 participants were enrolled and followed up at baseline, 24 h, 7 days, 14 days after EBRT initiation, at midpoint, and at completion of EBRT. Fatigue was measured by self-report using the Functional Assessment of Cancer Therapy - Fatigue (FACT-F), and cognitive impairment by the Computer Assessment of Mild Cognitive Impairment (CAMCI®)., Results: Subjects with increased fatigue during EBRT reported a significant decline in cognitive function and had difficulties with CAMCI®'s route finding and item recall tasks during EBRT. Increased fatigue during EBRT was associated with perceived cognitive difficulties in executive function and recognition memory, but not with attention or verbal memory., Conclusions: Our results suggest that there might be specific cognitive domains that are associated with increased fatigue during EBRT. These findings will provide important information for targeting specific cognitive domains using pharmacotherapy or behavioral interventions. CAMCI® is a valuable tool for psycho social providers to detect subtle cognitive impairment in fatigued cancer patients in a clinical setting., (© 2018 S. Karger AG, Basel.)

Fatigue, the most common side effect of cancer treatments, is observed to intensify during external-beam radiation therapy (EBRT). The underlying molecular mechanisms remain unclear. This study investigated the differentially expressed genes/proteins and their association with fatigue intensification during EBRT. Fatigue scores measured by FACT-F and peripheral blood were collected prior to treatment (baseline D 0 ), at midpoint (days 19-21, D21) and endpoint (days 38-42, D42) from men (n=30) with non-metastatic prostate cancer undergoing EBRT. RNA extracted from peripheral blood was used for gene expression analysis. Plasma arginase I and arginine were examined using ELISA and liquid chromatography-tandem mass spectrometry. Differences in fatigue scores, gene and protein expression between times points following EBRT were analyzed by one way ANOVA followed by Post Hoc t-test. Fatigue scores decreased significantly from baseline (44.6 ± 8.1) to midpoint (37.3 ± 10.6, p= 0.000, low scores indicating high fatigue) and to endpoint (37.4 ± 10.1, p=0.001) during EBRT. ARG1 (encoding arginase type 1) was significantly up regulated from baseline to midpoint of EBRT (fold change =2.41, p <0.05) whereas genes associated with the adaptive immune functional pathway ( CD28, CD27, CCR7, CD3D, CD8A and HLA-DOB ) were significantly downregulated >2-fold between the study time points. The changes in gene expression were associated with patient reported fatigue intensity. Moreover, the upregulation of ARG1 was negatively correlated with the absolute lymphocyte count (R 2 =0.561, p =0.01) only in the high level of fatigue group (n=17) during EBRT. Increased ARG1 expression is known to result in arginine deficiency, which leads to immunosuppression by impairing lymphocyte proliferation and activation. EBRT-induced ARG1 upregulation may play an essential role in fatigue intensification via the arginine deficiency and suppression of T-cell proliferation pathways. These findings may provide novel insights into the molecular-genetic mechanisms underlying the development and intensification of cancer treatment-related fatigue.

Objective: To examine the trajectory of fatigue experienced by 26 Puerto Rican (PR) men over the course of External Beam Radiation Therapy (EBRT) and to assess gene expression changes from baseline to midpoint of EBRT using microarray technology. Design/Research Approach- Prospective exploratory and comparative design study. Setting- RT facility located in San Juan, PR. Sample/Participants-26 PR men with non-metastatic prostate cancer., Methods: Participants completed 2 paper forms: demographics and the Spanish version of the 13-item FACT-fatigue at baseline, midpoint, and end of EBRT. Wholeblood samples were collected at baseline and at midpoint of EBRT. Descriptive data was analyzed using t-test, Wilcoxon, and Friedman test for repeated measures. Gene expression data was analyzed using the LIMMA package in R; the functional network analysis was conducted using Ingenuity Pathway analysis. Main Research Variable-Fatigue scores, gene expression., Results: Subjects were of ages 52-81 with fatigue scores that remained unchanged during EBRT (baseline=42.38, SD=9.34; midpoint=42.11, SD=8.93, endpoint=43.04, SD=8.62). Three hundred seventy-three genes (130-up regulated and 243-down regulated) were differentially expressed from baseline to mid-point of EBRT (FDR<0.01). The top distinct canonical pathways of the differentially expressed probesets (p<0.0001) were: "Phospholipase C Signaling," "Role of NFAT in Regulation of the Immune Response," and "Gαq Signaling.", Conclusion: While fatigue did not worsen over the course of EBRT for this sample as a group, there was variability in fatigue across the sample. It is possible that the over expression of the SESN3 gene, known to suppress oxidative damage, may have contributed to the attenuation of fatigue in this clinical population.

Fatigue affects most cancer patients and has numerous potential causes, including cancer itself and cancer treatment. Cancer-related fatigue (CRF) is not relieved by rest, can decrease quality of life, and has no FDA-approved therapy. Thyrotropin-releasing hormone (TRH) has been proposed as a potential novel treatment for CRF, but its efficacy against CRF remains largely untested. Thus, we tested the TRH analog, taltirelin (TAL), in mouse models of CRF. To model fatigue, we used a mouse model of chemotherapy, a mouse model of radiation therapy, and mice bearing colon 26 carcinoma tumors. We used the treadmill fatigue test to assess fatigue-like behavior after treatment with TAL. Additionally, we used wild-type and TRH receptor knockout mice to determine which TRH receptor was necessary for the actions of TAL. Tumor-bearing mice displayed muscle wasting and all models caused fatigue-like behavior, with mice running a shorter distance in the treadmill fatigue test than controls. TAL reversed fatigue-like behavior in all three models and the mouse TRH 1 receptor was necessary for the effects of TAL. These data suggest that TAL may be useful in alleviating fatigue in all cancer patients and provide further support for evaluating TAL as a potential therapy for CRF in humans., (Published by Elsevier Ltd.)

Fatigue is one of the most common and debilitating side effects of cancer and cancer treatment, and yet its etiology remains elusive. The goal of this study is to understand the role of chronic inflammation in fatigue following repeated stress from radiotherapy. Fatigue and non-fatigue categories were assessed using ≥ 3-point change in Functional Assessment of Cancer Therapy-Fatigue questionnaire (FACT-F) administered to participants at baseline/before radiotherapy and one year post-radiotherapy. Whole genome microarray and cytokine multiplex panel were used to examine fatigue-related transcriptome and serum cytokine changes, respectively. The study included 86 subjects (discovery phase n = 40, validation phase n = 46). The sample in the discovery phase included men with prostate cancer scheduled to receive external-beam radiotherapy. A panel of 48 cytokines were measured and the significantly changed cytokine found in the discovery phase was validated using sera from a separate cohort of men two years after completing radiotherapy for prostate cancer at a different institution. Effects of the significantly changed cytokine on cell viability was quantified using the MTT assay. During the discovery phase, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and TRAIL decoy receptor, TNFRSF10C (TRAIL-R3), were significantly upregulated in fatigued (≥3-point decrease from baseline to 1yr-post radiotherapy) subjects (n = 15). In the validation phase, TRAIL correlated with fatigue scores 2yrs post-radiotherapy. TRAIL caused selective cytotoxicity in neuronal cells, but not in microglial and muscle cells, in vitro. Late-onset inflammation directed by TRAIL may play a role in fatigue pathogenesis post-repeated stress from irradiation., (Published by Elsevier Ltd.)

Objective: Patient-reported health-related quality-of-life (HRQOL) measures can provide guidance for treatment decision making, symptom management, and discharge planning. HRQOL is often influenced by the distress experienced by patients from disease or treatment-related symptoms. This study aimed to identify symptoms that can predict changes in HRQOL in men undergoing external beam radiation therapy (EBRT) for nonmetastatic prostate cancer (NMPC)., Methods: Fifty-one men with NMPC scheduled for EBRT were assessed at the baseline, at the midpoint of EBRT, and at the end of EBRT. All participants received 38-42 daily doses of EBRT (five times a week), depending on the stage of their disease. Validated questionnaires were administered to evaluate depressive symptoms, urinary and sexual functions, bowel issues, symptom-related distress, fatigue, and HRQOL. Pearson correlations, repeated-measures ANOVA, and multiple regressions examined the relationships among variables., Results: Intensification of symptoms and increased symptom-related distress, with a corresponding decline in HRQOL, were observed during EBRT in men with NMPC. Changes in symptoms and symptom distress were associated with changes in HRQOL at the midpoint of EBRT ( r =-0.37 to -0.6, P =0.05) and at the end of EBRT ( r =-0.3 to -0.47, P =0.01) compared with the baseline. The regression model comprising age, body mass index, Gleason score, T category, androgen-deprivation therapy use, radiation dose received, symptoms (urinary/sexual/bowel problems, fatigue), and overall symptom distress explained 70% of the variance in predicting HRQOL. Urinary problems and fatigue significantly predicted the decline in HRQOL during EBRT., Conclusion: Identifying specific symptoms that can influence HRQOL during EBRT for NMPC can provide feasible interventional targets to improve treatment outcomes., Competing Interests: Conflict of interest The authors declare that they have no conflict of interest.

Background: Fatigue is one of the most debilitating adverse effects of cancer therapy. Identifying biomarkers early during cancer therapy may help us understand the biologic underpinnings of the persistence of fatigue following therapy., Objective: We aimed to identify early biomarkers of fatigue by examining correlations of levels of cytokines during external beam radiation therapy (EBRT) with persistence of fatigue 1 year following treatment completion in men with nonmetastatic prostate cancer (NM-PC)., Methods: A sample of 34 men with nonmetastatic prostate cancer scheduled to receive EBRT were followed up at baseline (T1), midpoint of EBRT (T2), and 1 year following EBRT (T3). Demographic and clinical data were obtained by chart review. The Functional Assessment of Cancer Therapy-Fatigue was administered to measure fatigue levels. Plasma cytokine levels were determined at T1 and T2 using the Bio-Rad Bio-Plex Cytokine Assay Kits., Results: Significant correlations were observed between levels of interleukin 2 (IL-3), IL-8, IL-9, IL-10, IL-16, interferon γ-induced protein 10, interferon α2, interferon γ, and stromal cell-derived factor 1α at T2 with worsening of fatigue from T1 to T3., Conclusions: Immunological changes prior to chronic fatigue development may reflect the long-term response to radiation therapy-induced damage., Implications for Practice: Early biomarkers for chronic fatigue related to cancer therapy will help advance our understanding of the etiology of this distressing symptom and will help nurses identify patients at risk of developing chronic fatigue after cancer treatment. This information will also aid in patient education, as well as symptom management.

Cancer-related fatigue (CRF) is a distressing and costly condition that often affects patients receiving cancer treatments, including radiation therapy. Here we describe a method using targeted peripheral irradiation to induce fatigue-like behavior in mice. With appropriate shielding, the irradiation targets the lower abdominal/pelvic region of the mouse, sparing the brain, in an effort to model radiation treatment received by individuals with pelvic cancers. We deliver an irradiation dose that is sufficient to induce fatigue-like behavior in mice, measured by voluntary wheel-running activity (VWRA), without causing obvious morbidity. Since wheel running is a normal, voluntary behavior in mice, its use should have little confounding effect on other behavioral tests or biological measures. Hence, wheel running can be used as a feasible outcome measure in understanding the behavioral and biological correlates of fatigue. CRF is a complex condition with frequent comorbidities, and likely has causes related both to cancer and its various treatments. The methods described in this paper are useful for investigating radiation-induced changes that contribute to the development of CRF and, more generally, to explore the biological networks that can explain the development and persistence of a peripherally-triggered but centrally-driven behavior like fatigue.

To better understand the impact of microarray preprocessing normalization techniques on the analysis of biological pathways in the prediction of chronic fatigue (CF) following radiation therapy, this study has compared the list of predictive genes found using the Robust Multiarray Averaging (RMA) and the Affymetrix MAS5 method, with the list that is obtained working with raw data (without any preprocessing). First, we modeled the spiked-in data set where differentially expressed genes were known and spiked-in at different known concentrations, showing that the precisions established by different gene ranking methods were higher than working with raw data. The results obtained from the spiked-in experiment were extrapolated to the CF data set to run learning and blind validation. RMA and MAS5 provided different sets of discriminatory genes that have a higher predictive accuracy in the learning phase, but lower predictive accuracy during the blind validation phase, suggesting that the genetic signatures generated using both preprocessing techniques cannot be generalizable. The pathways found using the raw data set better described what is a priori known for the CF disease. Besides, RMA produced more reliable pathways than MAS5. Understanding the strengths of these two preprocessing techniques in phenotype prediction is critical for precision medicine. Particularly, this article concludes that biological pathways might be better unraveled working with raw expression data. Moreover, the interpretation of the predictive gene profiles generated by RMA and MAS5 should be done with caution. This is an important conclusion with a high translational impact that should be confirmed in other disease data sets.

Context: Cancer-related fatigue (CRF) persists months after treatment completion. Although a CRF biomarker has not yet been identified, validated self-report questionnaires are used to define and phenotype CRF in the discovery of potential biomarkers., Objectives: The purposes of this study are to identify CRF subjects using three well-known CRF phenotyping approaches using validated self-report questionnaires and to compare the biologic profiles that are associated with each CRF phenotype., Methods: Fatigue in men with nonmetastatic prostate cancer receiving external beam radiation therapy was measured at baseline (T1), midpoint (T2), end point (T3), and one-year post-external beam radiation therapy (T4) using the Functional Assessment of Cancer Therapy-Fatigue (FACT-F) and Patient Reported Outcomes Measurement Information System-Fatigue. Chronic fatigue (CF) and nonfatigue subjects were grouped based on three commonly used phenotyping approaches: 1) T4 FACT-F <43; 2) T1-T4 decline in FACT-F score ≥3 points; 3) T4 Patient Reported Outcomes Measurement Information System-Fatigue T-score >50. Differential gene expressions using whole-genome microarray analysis were compared in each of the phenotyping criterion., Results: The study enrolled 43 men, where 34%-38% had CF based on the three phenotyping approaches. Distinct gene expression patterns were observed between CF and nonfatigue subjects in each of the three CRF phenotyping approaches: 1) Approach 1 had the largest number of differentially expressed genes and 2) Approaches 2 and 3 had 40 and 21 differentially expressed genes between the fatigue groups, respectively., Conclusion: The variation in genetic profiles for CRF suggests that phenotypic profiling for CRF should be carefully considered because it directly influences biomarker discovery investigations., (Published by Elsevier Inc.)

Objectives: Fatigue during cancer treatment is associated with depression. Neurotrophic factors play a major role in depression and stress and might provide insight into mechanisms of fatigue. This study investigated the association between plasma concentrations of three neurotrophic factors (BDNF, brain-derived neurotrophic factor; GDNF, glial-derived neurotrophic factor; and SNAPIN, soluble N-ethylmaleimide sensitive fusion attachment receptor-associated protein) and initial fatigue intensification during external beam radiation therapy (EBRT) in euthymic non-metastatic prostate cancer men., Methods: Fatigue, as measured by the 13-item Functional Assessment of Cancer Therapy-Fatigue (FACT-F), and plasma neurotrophic factors were collected at baseline (prior to EBRT) and mid-EBRT. Subjects were categorized into fatigue and no fatigue groups using a > 3-point change in FACT-F scores between the two time points. Multiple linear regressions analysed the associations between fatigue and neurotrophic factors., Results: FACT-F scores of 47 subjects decreased from baseline (43.95 ± 1.3) to mid-EBRT (38.36 ± 1.5, P < 0.001), indicating worsening fatigue. SNAPIN levels were associated with fatigue scores (r s = 0.43, P = 0.005) at baseline. A significant decrease of BDNF concentration (P = 0.008) was found in fatigued subjects during EBRT (n = 39)., Conclusions: Baseline SNAPIN and decreasing BDNF levels may influence worsening fatigue during EBRT. Further investigations are warranted to confirm their role in the pathophysiology and therapeutics of fatigue.

Objectives: Identification of biologic pathways of symptom clusters is necessary to develop precision therapies for distressing symptoms. This review examined extant literature evaluating relationships between biomarkers and symptom clusters in cancer survivors., Data Sources: PubMed, CINAHL, Web of Science and Cochrane Library were searched using terms "biological markers" or "biomarkers" and "symptom cluster" or "symptom complex" or "multiple symptoms.", Conclusion: Biomarkers related to inflammation (eg, cytokines) were the most studied and showed the most significant relationships with clusters of symptoms. This review suggests that clustering of symptoms related to cancer or cancer therapy is linked to immune/inflammatory pathways., Implications for Nursing Practice: Understanding the etiology of symptom clusters may guide future nursing interventions for symptom management., (Published by Elsevier Inc.)

Purpose: Fatigue is the most ubiquitous side effect of cancer treatment, but its etiology remains elusive. Further investigations into cancer-related fatigue pathobiology necessitate the expanded use of animal models. This study describes the development of a murine model of radiation-induced fatigue., Methods: Voluntary wheel running activity measured fatigue in 5-8 week-old, male C57BL/6 mice before and after γ irradiation totaling 2400cGy (3 consecutive days×800cGy daily fractionated doses) to the lower abdominal areas. Three trials confirmed fatigue behavior at this dose. Anhedonia, body weight, and hemoglobin were also measured. Gastrointestinal, skeletal muscle, and bone marrow tissue samples were evaluated for signs of damage., Results: In two validation trials, irradiated mice (trial 1, n=8; trial 2, n=8) covered less cumulative distance in kilometers post-irradiation (trial 1, mean=115.3±12.3; trial 2, mean=113.6±21.8) than sham controls (trial 1, n=5, mean=126.3±5.7, p=0.05; trial 2, n=8, mean=140.9±25.4, p=0.02). Decreased mean daily running distance and speed were observed during the last four hours of the dark cycle in irradiated mice compared to controls for two weeks post-irradiation. There were no differences in saccharin preference or hemoglobin levels between groups, no effect of changes in body weight or hemoglobin on wheel running distance, additionally, histology showed no damage to muscle, bone marrow, or gastrointestinal integrity, with the latter confirmed by ELISA., Conclusion: We characterized a novel mouse model of fatigue caused by peripheral radiation and not associated with anemia, weight changes, or anhedonia. This model provides opportunities for detailed study of the mechanisms of radiation-induced fatigue., (Published by Elsevier B.V.)

Purpose: The purpose of this study was to explore gene expression changes in fatigued men with nonmetastatic prostate cancer receiving localized external beam radiation therapy (EBRT)., Methods: Fatigue was measured in 40 men with prostate cancer (20 receiving EBRT and 20 controls on active surveillance) using the Functional Assessment of Cancer Therapy-Fatigue (FACT-F). EBRT subjects were followed from baseline to midpoint and end point of EBRT, while controls were seen at one time point. EBRT subjects were categorized into high- and low-fatigue groups based on change in FACT-F scores from baseline to EBRT completion. Full genome microarray was performed from peripheral leukocyte RNA to determine gene expression changes related to fatigue phenotypes. Real-time polymerase chain reaction and enzyme-linked immunosorbent assay confirmed the most differentially expressed gene in the microarray experiment., Results: At baseline, mean FACT-F scores were not different between EBRT subjects (44.3 ± 7.16) and controls (46.7 ± 4.32, p = .24). Fatigue scores of EBRT subjects decreased at treatment midpoint (38.6 ± 9.17, p = .01) and completion (37.6 ± 9.9, p = .06), indicating worsening fatigue. Differential expression of 42 genes was observed between fatigue groups when EBRT time points were controlled. Membrane-spanning four domains, subfamily A, member (MS4A1) was the most differentially expressed gene and was associated with fatigue at treatment end point (r = -.46, p = .04)., Conclusion: Fatigue intensification was associated with MS4A1 downregulation, suggesting that fatigue during EBRT may be related to impairment in B-cell immune response. The 42 differentially expressed fatigue-related genes are associated with glutathione biosynthesis, γ-glutamyl cycle, and antigen presentation pathways., (© The Author(s) 2015.)

Background: Fatigue is a multidimensional condition that is difficult to treat with standard monoaminergic antidepressants. Ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist produces rapid and robust improvements in depressive symptoms in treatment-resistant depression. However, there is a dearth of literature examining the anti-fatigue effects of ketamine. We hypothesize that ketamine will rapidly improve fatigue symptoms in treatment-resistant depressed patients., Methods: This is an exploratory analysis of data obtained from two double-blind, randomized, placebo-controlled, crossover trials. A total of 36 participants with treatment-resistant bipolar I or II disorder in a depressive episode (maintained on therapeutic levels of lithium or valproate) received a single infusion of ketamine hydrochloride intravenously (0.5 mg/kg over 40 min) or placebo. A post-hoc analysis compared fatigue scores on ketamine vs. placebo at 10 time points from baseline through 14 days post-treatment using the National Institute of Health-Brief Fatigue Inventory., Results: A linear mixed model showed that ketamine significantly lowered fatigue scores compared to placebo from 40 min post-treatment to Day 14 with the exception of Day 7. The largest difference in anti-fatigue effects between placebo and ketamine was at day 2 (d=0.58, p<0.05). The effect remained significant after controlling for changes in non-fatigue depressive symptoms., Limitation: The retrospective nature and a small sample size are study limitations., Conclusions: Ketamine rapidly improved fatigue relative to placebo in a group of individuals with treatment-resistant bipolar depression. NMDAR is a glutamate receptor; hence, glutamate may represent a valuable target to study the clinical efficacy of new anti-fatigue approaches in multiple disorders., (Published by Elsevier B.V.)

Objectives: To quantify the influence of abuse, particularly in childhood, with pain sensitivity and other adverse symptoms experienced by women with fibromyalgia (FM)., Methods: Subjects with FM completed a detailed abuse interview, dolorimetry, and questionnaire-based assessments of fatigue, cognitive self-appraisal, and depression. Student's t- and chi-square tests were used to analyse differences in FM symptoms between those with and without a history of childhood abuse. Linear regression was used to evaluate the relationship between abuse and symptom severity, adjusting for possible confounders., Results: In 111 women with FM, physical abuse during childhood demonstrated a clinically modest, yet statistically significant, association with increased tenderness as measured by pain pressure thresholds (β=-0.25, p=0.011) and tender points (β=0.23, p=.022). Physical child abuse was also associated with cognitive language impairment after adjusting for depression (β=0.27, p=0.001). While emotional child abuse was associated with fatigue, the association did not persist after adjustment for depressive symptoms., Conclusions: Group differences are of small magnitude and might not directly impact clinical practice, however, the experience of child abuse is associated with FM symptom severity and may shape the biological development of interoception in ways that predispose to pain and polysymptomatic distress.

Fatigue is one of the most common side-effects accompanying radiotherapy, but arguably the least understood. Radiotherapy-induced fatigue (RIF) is a clinical subtype of cancer treatment-related fatigue. It is described as a pervasive, subjective sense of tiredness persisting over time, interferes with activities of daily living, and is not relieved by adequate rest or sleep. RIF is one of the early side-effects and long-lasting for cancer patients treated with localized radiation. Although the underlying mechanisms of fatigue have been studied in several disease conditions, the etiology, mechanisms, and risk factors of RIF remain elusive, and this symptom remains poorly managed. The purpose of this paper is to review and discuss recent articles that defined, proposed biologic underpinnings and mechanisms to explain the pathobiology of RIF, as well as articles that proposed interventions to manage RIF. Understanding the mechanisms of RIF can describe promising pathways to identify at-risk individuals and identify potential therapeutic targets to alleviate and prevent RIF using a multimodal, multidisciplinary approach., Competing Interests: Declaration of interest The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.

Objective: To develop a symptoms cluster model that can describe factors of fibromyalgia syndrome (FMS) associated with fatigue severity as reported by the sample and to explore FMS clinical symptom subclusters based on varying symptom intensities., Methods: FMS individuals (n = 120, 82% ages 31-60 years, 90% women, 59% white) diagnosed with the 1990 or 2010 American College of Rheumatology diagnostic criteria were enrolled. Participants completed multiple validated self-report questionnaires to measure fatigue, pain, depression, anxiety, pain catastrophizing, daytime sleepiness, cognitive function, and FMS-related polysymptomatic distress. Cluster analysis using SPSS 19.0 and structural equation modeling using AMOS 17.0 were used., Results: Final structural equation modeling the symptoms cluster model showed good fit and revealed that FMS fatigue was associated with widespread pain, symptoms severity, pain intensity, pain interference, cognitive dysfunction, catastrophizing, anxiety, and depression (χ(2)  = 121.72 (98df), P > 0.05, χ(2) /df = 1.242, comparative fit index = 0.982, root mean square error of approximation = 0.045). Two distinct clinical symptom subclusters emerged: subcluster 1 (78% of total subjects), defined by widespread pain, unrefreshed waking, and somatic symptoms, and subcluster 2 (22% of total subjects), defined by fatigue and cognitive dysfunction with pain being a less severe and less widespread occurrence., Conclusion: Overall, subcluster 1 had more intense symptoms than subcluster 2. FMS symptoms may be categorized into 2 clinical subclusters. These findings have implications for an illness whose diagnosis and management are symptom dependent. A longitudinal study capturing the variability in the symptom experience of FMS subjects is warranted., (© 2016, American College of Rheumatology.)

Background: Fatigue is one of the most distressing symptoms experienced by people with cancer receiving radiation therapy., Objectives: The goal of this study is to evaluate clinical predictors of worsening fatigue during external beam radiation therapy (EBRT) in men with non-metastatic prostate cancer., Methods: Thirty-five men with non-metastatic prostate cancer scheduled for EBRT were followed at baseline, midpoint, and completion of EBRT. The Functional Assessment of Cancer Therapy-Fatigue scale was administered. Demographic and clinical data were obtained by chart review. Paired t-tests, correlations, general linear models, and logistic regressions were used to determine associations between fatigue scores and clinical data., Findings: Red blood cells, hemoglobin, and hematocrit levels were highly intercorrelated and, therefore, were grouped as one composite variable termed heme. Heme levels at baseline and androgen-deprivation therapy (ADT) were significantly correlated with worsening of fatigue symptoms from baseline to midpoint and endpoint. ADT alone did not have a significant correlation with fatigue, but it indirectly affected fatigue levels by influencing heme markers as treatment progressed. These findings provide evidence that hematologic markers and the use of ADT assist in predicting radiation therapy-related fatigue and guide symptom management.

Objective: Fatigue is a complex, multidimensional condition. Although it is often associated with depression, it is not known whether it has a distinct network from depression or whether it can be clinically evaluated, separately. This study describes preliminary findings in the development of a brief, clinician-administered instrument to measure fatigue in the context of depressive disorders using items from existing clinician-administered depression and mania scales., Methods: Based on items from prior fatigue measurements, items were selected from the Hamilton Depression Rating Scale (HDRS), Montgomery-Asberg Depression Rating Scale (MADRS), Young Mania Rating Scale, and Structured Interview Guide for HDRS with Atypical Depression. The final items composed the NIH-Brief Fatigue Inventory (NIH-BFI). Responses from 89 depressed adults collected pre- and post-antidepressant therapy (ADT) determined the reliability and consistency of the NIH-BFI using Cronbach's alpha and principal components analysis (PCA). Correlations of the NIH-BFI and fatigue items from other scales before and after ADT explored validity., Results: The 7-item NIH-BFI had Cronbach alphas ranging from 0.81 to 0.88 and PCA indicating a single dimension. The NIH-BFI score was strongly correlated (r = 0.73, p < 0.001) with fatigue items from Beck Depression Index, with MADRS without fatigue items (r = 0.77, p < 0.001), and HDRS without fatigue items (pre: r = 0.69, p < 0.001)., Conclusions: Preliminary findings show support for internal consistency reliability and validity of the NIH-BFI, a clinician-administered measure of fatigue. Further testing in other clinical populations is recommended to obtain additional information on reliability and validity. The NIH-BFI provides a method for clinician-rated fatigue that may be a separate from depression., (Published by Elsevier Ltd.)

Purpose: Understanding the etiology of cancer-related fatigue (CRF) is critical to identify targets to develop therapies to reduce CRF burden. The goal of this systematic review was to expand on the initial work by the National Cancer Institute CRF Working Group to understand the state of the science related to the biology of CRF and, specifically, to evaluate studies that examined the relationships between biomarkers and CRF and to develop an etiologic model of CRF to guide researchers on pathways to explore or therapeutic targets to investigate., Methods: This review was completed by the Multinational Association of Supportive Care in Cancer Fatigue Study Group-Biomarker Working Group. The initial search used three terms (biomarkers, fatigue, cancer), which yielded 11,129 articles. After removing duplicates, 9145 articles remained. Titles were assessed for the keywords "cancer" and "fatigue" resulting in 3811 articles. Articles published before 2010 and those with samples <50 were excluded, leaving 75 articles for full-text review. Of the 75 articles, 28 were further excluded for not investigating the associations of biomarkers and CRF., Results: Of the 47 articles reviewed, 25 were cross-sectional and 22 were longitudinal studies. More than half (about 70 %) were published recently (2010-2013). Almost half (45 %) enrolled breast cancer participants. The majority of studies assessed fatigue using self-report questionnaires, and only two studies used clinical parameters to measure fatigue., Conclusions: The findings from this review suggest that CRF is linked to immune/inflammatory, metabolic, neuroendocrine, and genetic biomarkers. We also identified gaps in knowledge and made recommendations for future research.

Background: Fibromyalgia syndrome (FMS), a chronic musculoskeletal condition characterized by diffuse pain, fatigue, sleep impairment, and cognitive dysfunction, is associated with significant functional disability. Its underlying biological mechanisms are unknown. This study investigated differentially expressed genes between women with FMS and healthy volunteers., Methods: Women who met the 1990 or 2010 American College of Rheumatology fibromyalgia criteria were compared to age- and race-matched pain-free healthy women. Peripheral blood samples were collected, and a full genome microarray gene expression analysis was performed. One-way analysis of variance was used to identify differentially expressed genes using the filtering criterion of 1% false discovery rate. Analysis of canonical pathways associated with these genes was performed. Confirmatory quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assay verified microarray results. Independent t-tests compared gene and protein expression between groups., Result: Participants were 54 women with FMS and 25 controls. Expression arrays from a subset of women with FMS (n = 29) and controls (n = 20) showed upregulation of 12 genes (>1.8-fold change, p < .05) in the FMS sample. Differentially expressed genes were related to B-cell development, primary immunodeficiency signaling, and mitotic roles of polo-like kinase. CENPK and HSP90AA1 were the most differentially expressed genes (p < .01)., Conclusion: Activity of interrelated pathways related to immune response, and homeostasis appears to be relevant to the experience of FMS. Replication and exploration of the relationship between gene expression and symptom severity will help determine clinical relevance of these findings., (© The Author(s) 2015.)

Background: Shank3, a post-synaptic density protein involved in N-methyl-d-aspartate (NMDA) receptor tethering and dendritic spine rearrangement, is implicated in the pathophysiology of bipolar disorder. We hypothesized that elevated baseline plasma Shank3 levels might predict antidepressant response to the NMDA receptor antagonist ketamine., Methods: Twenty-nine subjects with bipolar depression received a double-blind, randomized, subanesthetic dose (.5 mg/kg) ketamine infusion. Of the patients for whom Shank3 levels were collected, 15 completed baseline 3-Tesla MRI and 17 completed post-ketamine [(18)F]-FDG PET., Results: Higher baseline Shank3 levels predicted antidepressant response at Days 1 (r=-.39, p=.047), 2 (r=-.45, p=.02), and 3 (r=-.42, p=.03) and were associated with larger average (r=.58, p=.02) and right amygdala volume (r=.65, p=.009). Greater baseline Shank3 also predicted increased glucose metabolism in the hippocampus (r=.51, p=.04) and amygdala (r=.58, p=.02)., Limitations: Limitations include the small sample size, inability to assess the source of peripheral Shank3, and the lack of a placebo group for baseline Shank3 levels and comparative structural/functional neuroimaging., Conclusions: Shank3 is a potential biomarker of antidepressant response to ketamine that correlates with baseline amygdala volume and increased glucose metabolism in the amygdala and hippocampus., (Published by Elsevier B.V.)

Background: Fatigue is a common side effect of cancer (CA) treatment. We used a novel analytical method to identify and validate a specific gene cluster that is predictive of fatigue risk in prostate cancer patients (PCP) treated with radiotherapy (RT)., Methods: A total of 44 PCP were categorized into high-fatigue (HF) and low-fatigue (LF) cohorts based on fatigue score change from baseline to RT completion. Fold-change differential and Fisher's linear discriminant analyses (LDA) from 27 subjects with gene expression data at baseline and RT completion generated a reduced base of most discriminatory genes (learning phase). A nearest-neighbor risk (k-NN) prediction model was developed based on small-scale prognostic signatures. The predictive model validity was tested in another 17 subjects using baseline gene expression data (validation phase)., Result: The model generated in the learning phase predicted HF classification at RT completion in the validation phase with 76.5% accuracy., Conclusion: The results suggest that a novel analytical algorithm that incorporates fold-change differential analysis, LDA, and a k-NN may have applicability in predicting regimen-related toxicity in cancer patients with high reliability, if we take into account these results and the limited amount of data that we had at disposal. It is expected that the accuracy will be improved by increasing data sampling in the learning phase.

Introduction: There is limited information on the knowledge, perceptions, beliefs, and practice, about genetics and genomics among Filipino-American nurses. The National Coalition of Ethnic Minority Organizations (NCEMNA), in which the Philippine Nurses Association of America (PNAA) is a member organization, conducted an online survey to describe the genomic knowledge, perceptions, beliefs, and practice of minority nurses. This study reports on responses from Filipino-American survey participants, which is a subset analysis of the larger NCEMNA survey., Objective: The purpose of this study was to explore the knowledge, perceptions, beliefs, practice and genomic education of Filipino-American nurses., Method: An online survey of 112 Filipino-American nurses was conducted to describe the knowledge, perceptions, beliefs, and practice of genetics/genomics. Survey responses were analyzed using descriptive statistics., Results: Most (94%) Filipino-American nurses wanted to learn more about genetics. Although 41% of the respondents indicated good understanding of genetics of common diseases, 60% had not attended any related continuing education courses since RN licensure, and 73% reported unavailability of genetic courses to take. The majority (83%) of PNAA respondents indicated that they would attend genetics/genomics awareness training if it was offered by their national organization during their annual conference, and 86% reported that the national organization should have a visible role in genetics/genomics initiatives in their community., Conclusion: Filipino-American nurses wanted to learn more about genetics and were willing to attend genetics/genomics trainings if offered by PNAA. The study findings can assist PNAA in planning future educational programs that incorporates genetics and genomics information.

Fatigue is often described by patients as a lack of energy, mental or physical tiredness, diminished endurance, and prolonged recovery after physical activity. Etiologic mechanisms underlying fatigue are not well understood; however, fatigue is a hallmark symptom of mitochondrial disease, making mitochondrial dysfunction a putative biological mechanism for fatigue. Therefore, this review examined studies that investigated the association of markers of mitochondrial dysfunction with fatigue and proposes possible research directions to enhance understanding of the role of mitochondrial dysfunction in fatigue. A thorough search using PubMed, Scopus, Web of Science, and Embase databases returned 1,220 articles. After application of inclusion and exclusion criteria, a total of 25 articles meeting eligibility criteria were selected for full review. Dysfunctions in the mitochondrial structure, mitochondrial function (mitochondrial enzymes and oxidative/nitrosative stress), mitochondrial energy metabolism (ATP production and fatty acid metabolism), immune response, and genetics were investigated as potential contributors to fatigue. Carnitine was the most investigated mitochondrial function marker. Dysfunctional levels were reported in all the studies investigating carnitine; however, the specific type of carnitine that was dysfunctional varied. Genetic profiles were the second most studied mitochondrial parameter. Six common pathways were proposed: metabolism, energy production, protein transport, mitochondrial morphology, central nervous system dysfunction and post-viral infection. Coenzyme Q10 was the most commonly investigated mitochondrial enzyme. Low levels of Coenzyme Q10 were consistently associated with fatigue. Potential targets for further investigation were identified as well as gaps in the current literature.

Context: Fatigue is the most distressing side effect of radiation therapy, and its progression etiology is unknown., Objectives: This study describes proteome changes from sera of fatigued men with non-metastatic prostate cancer receiving external beam radiation therapy (EBRT)., Methods: Fatigue scores, measured by the Functional Assessment of Chronic Illness Therapy-Fatigue, and serum were collected from 12 subjects at baseline (before EBRT) and at midpoint (Day 21) of EBRT. Depleted sera from both time points were analyzed using two-dimensional difference gel electrophoresis, and up/down regulated proteins were identified using liquid chromatography-tandem mass spectrometry. Western blot analyses confirmed the protein changes observed., Results: Results showed that apolipoprotein (Apo)A1, ApoE, and transthyretin (TTR) consistently changed from baseline (Day 0) to midpoint (Day 21). The mean ApoE level of subjects with high change in fatigue (HF: n = 9) increased significantly from baseline to midpoint and were higher than in subjects with no change in fatigue. The mean ApoA1 level was higher in HF subjects at baseline and at midpoint than in no fatigue subjects at both time points. The mean TTR level of no fatigue subjects was higher at baseline and midpoint than in HF subjects., Conclusion: These ApoE, ApoA1, and TTR results may assist in understanding pathways that can explain fatigue progression etiology in this clinical population., (Published by Elsevier Inc.)