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Gene Expression Profiling of Evening Fatigue in Women Undergoing Chemotherapy for Breast Cancer

Kober, Kord M; Dunn, Laura; Mastick, Judy; Cooper, Bruce; Langford, Dale; Melisko, Michelle; Venook, Alan; Chen, Lee-May; Wright, Fay; Hammer, Marilyn; Schmidt, Brian L; Levine, Jon; Miaskowski, Christine; Aouizerat, Bradley E
Moderate-to-severe fatigue occurs in up to 94% of oncology patients undergoing active treatment. Current interventions for fatigue are not efficacious. A major impediment to the development of effective treatments is a lack of understanding of the fundamental mechanisms underlying fatigue. In the current study, differences in phenotypic characteristics and gene expression profiles were evaluated in a sample of breast cancer patients undergoing chemotherapy (CTX) who reported low (n = 19) and high (n = 25) levels of evening fatigue. Compared to the low group, patients in the high evening fatigue group reported lower functional status scores, higher comorbidity scores, and fewer prior cancer treatments. One gene was identified as upregulated and 11 as downregulated in the high evening fatigue group. Gene set analysis found 24 downregulated and 94 simultaneously up- and downregulated pathways between the two fatigue groups. Transcript origin analysis found that differential expression (DE) originated primarily from monocytes and dendritic cell types. Query of public data sources found 18 gene expression experiments with similar DE profiles. Our analyses revealed that inflammation, neurotransmitter regulation, and energy metabolism are likely mechanisms associated with evening fatigue severity; that CTX may contribute to fatigue seen in oncology patients; and that the patterns of gene expression may be shared with other models of fatigue (e.g., physical exercise and pathogen-induced sickness behavior). These results suggest that the mechanisms that underlie fatigue in oncology patients are multifactorial.
PMCID:5575784
PMID: 26957308
ISSN: 1552-4175
CID: 2046642

Vitamin D Deficiency Is Associated With Increased Risk of Non-alcoholic Steatohepatitis in Adults With Non-alcoholic Fatty Liver Disease: Possible Role for MAPK and NF-kappaB?

Nelson, James E; Roth, Christian L; Wilson, Laura A; Yates, Katherine P; Aouizerat, Bradley; Morgan-Stevenson, Vicki; Whalen, Elizabeth; Hoofnagle, Andrew; Mason, Michael; Gersuk, Vivian; Yeh, Matthew M; Kowdley, Kris V
OBJECTIVES: The objective of this study was to determine the relationship of serum vitamin D deficiency (VDD) to histologic features of non-alcoholic fatty liver disease (NAFLD), and associated demographic, clinical, laboratory, and transcriptomic data in the well-characterized Non-alcoholic Steatohepatitis Clinical Research Network (NASH CRN) cohort. METHODS: Serum vitamin D 25(OH)D (VD) was quantified by liquid chromatography-tandem mass spectrometry in 190 adults (>18 years) with biopsy-proven NAFLD. Subjects were categorized according to their level of VD as either sufficient (>30 ng/ml), insufficient (>/=20
PMCID:5361650
PMID: 27002799
ISSN: 1572-0241
CID: 2625552

A Rasch Analysis of Assessments of Morning and Evening Fatigue in Oncology Patients Using the Lee Fatigue Scale

Lerdal, Anners; Kottorp, Anders; Gay, Caryl; Aouizerat, Bradley E; Lee, Kathryn A; Miaskowski, Christine
CONTEXT: To accurately investigate diurnal variations in fatigue, a measure needs to be psychometrically sound and demonstrate stable item function in relationship to time of day. Rasch analysis is a modern psychometric approach that can be used to evaluate these characteristics. OBJECTIVES: To evaluate, using Rasch analysis, the psychometric properties of the Lee Fatigue Scale (LFS) in a sample of oncology patients. METHODS: The sample comprised 587 patients (mean age 57.3+/-11.9 years, 80% female) undergoing chemotherapy for breast, gastrointestinal, gynecological, or lung cancer. Patients completed the 13-item LFS within 30 minutes of awakening (i.e., morning fatigue) and prior to going to bed (i.e., evening fatigue). Rasch analysis was used to assess validity and reliability. RESULTS: In initial analyses of differential item function, eight of the 13 items functioned differently depending on whether the LFS was completed in the morning or in the evening. Subsequent analyses were conducted separately for the morning and evening fatigue assessments. Nine of the morning fatigue items and 10 of the evening fatigue items demonstrated acceptable goodness-of-fit to the Rasch model. Principal components analyses indicated that both morning and evening assessments demonstrated unidimensionality. Person separation indices indicated that both morning and evening fatigue scales were able to distinguish four distinct strata of fatigue severity. CONCLUSION: Excluding four items from the morning fatigue scale and three items from the evening fatigue scale improved the psychometric properties of the LFS for assessing diurnal variations in fatigue severity in oncology patients.
PMCID:4902715
PMID: 26975624
ISSN: 1873-6513
CID: 2047102

Differences in demographic, clinical, and symptom characteristics and quality of life outcomes among oncology patients with different types of pain

Posternak, Victoria; Dunn, Laura B; Dhruva, Anand; Paul, Steven M; Luce, Judith; Mastick, Judy; Levine, Jon D; Aouizerat, Bradley E; Hammer, Marylin; Wright, Fay; Miaskowski, Christine
The purposes of this study, in oncology outpatients receiving chemotherapy (n = 926), were to: describe the occurrence of different types of pain (ie, no pain, only noncancer pain [NCP], only cancer pain [CP], or both CP and NCP) and evaluate for differences in demographic, clinical, and symptom characteristics, and quality of life (QOL) among the 4 groups. Patients completed self-report questionnaires on demographic and symptom characteristics and QOL. Patients who had pain were asked to indicate if it was or was not related to their cancer or its treatment. Medical records were reviewed for information on cancer and its treatments. In this study, 72.5% of the patients reported pain. Of the 671 who reported pain, 21.5% reported only NCP, 37.0% only CP, and 41.5% both CP and NCP. Across the 3 pain groups, worst pain scores were in the moderate to severe range. Compared with the no pain group, patients with both CP and NCP were significantly younger, more likely to be female, have a higher level of comorbidity, and a poorer functional status. In addition, these patients reported: higher levels of depression, anxiety, fatigue, and sleep disturbance; lower levels of energy and attentional function; and poorer QOL. Patients with only NCP were significantly older than the other 3 groups. The most common comorbidities in the NCP group were back pain, hypertension, osteoarthritis, and depression. Unrelieved CP and NCP continue to be significant problems. Oncology outpatients need to be assessed for both CP and NCP conditions.
PMCID:4939771
PMID: 26683234
ISSN: 1872-6623
CID: 2031472

Subgroups of chemotherapy patients with distinct morning and evening fatigue trajectories

Kober, Kord M; Cooper, Bruce A; Paul, Steven M; Dunn, Laura B; Levine, Jon D; Wright, Fay; Hammer, Marilyn J; Mastick, Judy; Venook, Alan; Aouizerat, Bradley E; Miaskowski, Christine
PURPOSE: Purposes of this study were to identify subgroups of patients with distinct trajectories for morning and evening fatigue, evaluate for differences in demographic and clinical characteristics among these subgroups, and compare and contrast the predictors of subgroup membership for morning and evening fatigue. METHODS: Outpatients with breast, gastrointestinal, gynecological, or lung cancer (n = 582) completed questionnaires, a total of six times over two cycles of chemotherapy (CTX). Morning and evening fatigue severity were evaluated using the Lee Fatigue Scale. Latent profile analysis (LPA) was used to identify distinct subgroups. RESULTS: Three latent classes were identified for morning fatigue (i.e., low (31.8 %), high (51.4 %), and very high (16.8 %)) and for evening fatigue (i.e., moderate (20.0 %), high (21.8 %), and very high (58.2 %)). Most of the disease and treatment characteristics did not distinguish among the morning and evening fatigue classes. Compared to the low class, patients in the high and very high morning fatigue classes were younger, had a lower functional status, and higher level of comorbidity. Compared to the moderate class, patients in the very high evening fatigue class were younger, more likely to be female, had child care responsibilities, had a lower functional status, and a higher level of comorbidity. CONCLUSION: LPA allows for the identification of risk factors for more severe fatigue. Since an overlap was not observed across the morning and evening fatigue classes and unique predictors for morning and evening fatigue were identified, these findings suggest that morning and evening fatigue may have distinct underlying mechanisms.
PMCID:5473960
PMID: 26361758
ISSN: 1433-7339
CID: 1788082

Polymorphisms in Tumor Necrosis Factor-alpha Are Associated With Higher Anxiety Levels in Women After Breast Cancer Surgery

Miaskowski, Christine; Elboim, Charles; Paul, Steven M; Mastick, Judy; Cooper, Bruce A; Levine, Jon D; Aouizerat, Bradley E
INTRODUCTION: Before and after breast cancer surgery, women have reported varying anxiety levels. Recent evidence has suggested that anxiety has a genetic basis and is associated with inflammation. The purposes of the present study were to identify the subgroups of women with distinct anxiety trajectories; to evaluate for differences in the phenotypic characteristics between these subgroups; and to evaluate for associations between polymorphisms in cytokine genes and subgroup membership. PATIENTS AND METHODS: Patients with breast cancer (n = 398) were recruited before surgery and followed up for 6 months. The patients completed the Spielberger State Anxiety Inventory and provided a blood sample for genomic analyses. Growth mixture modeling was used to identify the subgroups of patients with distinct anxiety trajectories. RESULTS: Two distinct anxiety subgroups were identified. The women in the higher anxiety subgroup were younger and had a lower functional status score. Two single nucleotide polymorphisms in tumor necrosis factor-alpha (rs1799964, rs3093662) were associated with the higher anxiety subgroup. CONCLUSION: The results of the present exploratory study suggest that polymorphisms in cytokine genes could partially explain the interindividual variability in anxiety. The determination of phenotypic and molecular markers associated with greater levels of anxiety can assist clinicians to identify high-risk patients and initiate appropriate interventions.
PMID: 25813148
ISSN: 1938-0666
CID: 1563422

Comparison of subgroups of breast cancer patients on pain and co-occurring symptoms following chemotherapy

Langford, Dale J; Paul, Steven M; Cooper, Bruce; Kober, Kord M; Mastick, Judy; Melisko, Michelle; Levine, Jon D; Wright, Fay; Hammer, Marilyn J; Cartwright, Frances; Lee, Kathryn A; Aouizerat, Bradley E; Miaskowski, Christine
PURPOSE: The purposes of this study, in a sample of women with breast cancer receiving chemotherapy (CTX), were to identify subgroups of women with distinct experiences with the symptom cluster of pain, fatigue, sleep disturbance, and depressive symptoms and evaluate differences in demographic and clinical characteristics, differences in psychological symptoms, and differences in pain characteristics among these subgroups. METHODS: Patients completed symptom questionnaires in the week following CTX administration. Latent class profile analysis (LCPA) was used to determine the patient subgroups. RESULTS: Three subgroups were identified: 140 patients (35.8 %) in the "low," 189 patients (48.3 %) in the "moderate," and 62 patients (15.9 %) in the "all high" latent class. Patients in the all high class had a lower functional status, a higher comorbidity profile, a higher symptom burden, and a poorer quality of life. CONCLUSIONS: Study findings provide evidence of the utility of LCPA to explain inter-individual variability in the symptom experience of patients undergoing CTX. The ability to characterize subgroups of patients with distinct symptom experiences allows for the identification of high-risk patients and may guide the design of targeted interventions that are tailored to an individual's symptom profile.
PMID: 26142303
ISSN: 1433-7339
CID: 1650842

Differences in the Molecular Species of CA125 Across the Phases of the Menstrual Cycle

McLemore, Monica R; Miaskowski, Christine; Lee, Kathryn; Chen, Lee-May; Aouizerat, Bradley E
BACKGROUND: CA125, a tumor-associated antigen, is primarily used to monitor epithelial ovarian cancer. There is evidence that different species of CA125 exist; however, it is not known if any of these species are present in healthy women during the menstrual cycle and if they are associated with serum concentrations of CA125. The purpose of this study was to determine if the molecular species of CA125 differ across the three phases of the menstrual cycle in healthy women. METHODS: Healthy, Caucasian women between the ages of 18 and 39 were enrolled using strict criteria to exclude factors known to contribute to CA125 fluctuations. Menstrual cycle regularity was determined using calendars maintained by participants for 3 months. After cycle regularity was established, blood was drawn at three time points for Western blot analysis. RESULTS: Western blot analysis yielded 17 distinct profiles (i.e., patterns of species) of CA125, with 80% of the sample exhibiting 5 common profiles. No differences in demographic characteristics and serum CA125 values were found among the various CA125 profiles. CONCLUSIONS: Different molecular species of CA125 exist in healthy women with regular menstrual cycles. These data provide evidence that CA125 is not a homogeneous molecular species. Future research should evaluate the molecular composition and the clinical importance of these species.
PMID: 25566791
ISSN: 1552-4175
CID: 1563392

Glycosylated Hemoglobin A1c and Lack of Association With Symptom Severity in Patients Undergoing Chemotherapy for Solid Tumors

Hammer, Marilyn J; Aouizerat, Bradley E; Schmidt, Brian L; Cartwright, Frances; Wright, Fay; Miaskowski, Christine
PURPOSE/OBJECTIVES: To assess the effects of high blood sugar at the levels of diabetic or prediabetic states during cancer treatment because patients undergoing chemotherapy (CTX) experience multiple symptoms that vary among individuals and may be affected by glucose levels. DESIGN: Descriptive, cross-sectional. SETTING: Two comprehensive cancer centers, one Veterans Affairs hospital, and four community-based oncology programs. SAMPLE: 244 outpatients with breast, gastrointestinal, gynecologic, and lung cancers. METHODS: Patients completed demographic and symptom questionnaires. Glycosylated hemoglobin A1c (HbA1c) was evaluated to determine diabetic state. Descriptive statistics and one-way analyses of variance were used in the analyses. MAIN RESEARCH VARIABLES: HbA1c, symptom severity scores, patient and clinical characteristics (e.g., age, gender, comorbidities, sociodemographic information, body mass index [BMI], lifestyle factors). FINDINGS: HbA1c results showed 9% of the sample in the diabetic and 26% in the prediabetic state. Patients in the diabetic state reported a higher number of comorbid conditions and were more likely to be African American. Patients in the prediabetic state were older aged. Patients in the diabetic and prediabetic states had a higher BMI compared to nondiabetic patients. No differences in symptom severity or quality-of-life (QOL) scores were found among the three diabetic states. CONCLUSIONS: This study is the first to evaluate for associations between diabetic states and symptom severity and QOL scores in patients receiving CTX. This study confirmed that older age, as well as having higher BMI and having multiple comorbidities, were associated with increased mean glycemic levels. IMPLICATIONS FOR NURSING: Clinicians should assess and identify patients with diabetes or prediabetes undergoing treatment for cancer. Patients who are older aged, those with a high BMI, and those with multiple comorbid conditions may be at increased risk for higher glycemic states.
PMID: 26488828
ISSN: 1538-0688
CID: 1810232

Phenotypic and Molecular Evidence Suggest That Decrements in Morning and Evening Energy Are Distinct But Related Symptoms

Aouizerat, Bradley E; Dhruva, Anand; Paul, Steven M; Cooper, Bruce A; Kober, Kord M; Miaskowski, Christine
CONTEXT: Little is known about energy levels in oncology patients and their family caregivers (FCs). OBJECTIVES: This study sought to identify latent classes of participants, based on self-reported energy levels and to evaluate for differences in phenotypic and genotypic characteristics between these classes. METHODS: Energy subscale scores from the Lee Fatigue Scale were used to determine latent class membership. Morning and evening energy scores were obtained just prior to, during, and for four months following the completion of radiation therapy. Genetic associations were evaluated for fifteen pro- and anti-inflammatory cytokine genes. RESULTS: Two latent classes with distinct morning energy trajectories were identified. Participants who were younger, female, not married/partnered, Black, and had more comorbidities, and a lower functional status were more likely to be in the Low Morning Energy class. Two polymorphisms (IL2 rs1479923, NFKB1 rs4648110) were associated with morning energy latent class membership. Two latent classes with distinct evening energy trajectories were identified. Participants who were younger and male and who had more comorbidities, decreased body weight, and a lower functional status were more likely to be in the Moderate Evening Energy class. Five different polymorphisms (IL1R2 rs4141134, IL6 rs4719714, IL17A rs8193036, NFKB2 rs1056890, TNFA rs1800683) were associated with evening energy latent class membership. CONCLUSION: This study provides preliminary evidence that decrements in morning and evening energy are associated with different phenotypic risk factors as well as cytokine gene variations.
PMCID:4624028
PMID: 26031709
ISSN: 1873-6513
CID: 1615292