MicroRNA Profiles in Hematopoietic Stem Cell Transplant Recipients.

Background: Hematopoietic Stem Cell Transplant (HCT) is a potentially curative treatment for hematologic malignancies, including multiple myeloma. Biomarker investigation can guide identification of HCT recipients at-risk for poor outcomes. MicroRNAs (miRNAs) are a class of non-coding RNAs involved in the modulation and regulation of pathological processes and are emerging as prognostic and predictive biomarkers for multiple health conditions. This pilot study aimed to examine miRNA profiles associated with HCT-related risk factors and outcomes in patients undergoing autologous HCT. Methods: Patients eligible for autologous HCT were recruited and blood samples and HCT-related variables were collected. Differential expression analysis of miRNA was conducted on 24 patient samples to compare changes in miRNA profile in HCT eligible patients before and after transplant. Results: Unsupervised clustering of differentially expressed (p < .05) miRNAs pre- and post- HCT identified clusters of up- and down-regulated miRNAs. Four miRNAs (miR-125a-5p, miR-99b-5p, miR-382-5p, miR-145-5p) involved in hematopoiesis (differentiation of progenitor cells, granulocyte function, thrombopoiesis, and tumor suppression) were significantly downregulated post-HCT. Correlation analyses identified select miRNAs associated with risk factors (such as frailty, fatigue, cognitive decline) and quality of life pre- and post-HCT. Select miRNAs were correlated with platelet engraftment. Conclusion: Future studies should examine miRNA signatures in larger cohorts in association with HCT outcomes; and expand investigations in patients receiving allogeneic transplants. This will lead to identification of biomarkers for risk stratification of HCT recipients.

Challenges and opportunities faced by nurse scientists in integrating data and technology in research to promote health equity.

Advances in technologies including omics, apps, imaging, sensors, and big data are increasingly being integrated into research by nurse scientists, but the impact on improving health equity is still unclear. In this article, nursing research faculty from one institution discuss challenges and opportunities experienced when integrating various technologies into their research aimed at promoting health equity. Using exemplars from faculty experiences, a three-pronged approach to keeping patients and communities and the goal of health equity central in research while incorporating advancing technologies is described. This approach includes establishing long-term engagement with populations underrepresented in research, adopting strategies to increase diversity in study participant recruitment, and training and collaboration among a diverse workforce of educators, clinicians, and researchers. Training nurse scientists in integrating data and technology for advancing the science on health equity will shift the culture of how we understand, collaborate, and grow with the communities in which we train and practice as nurse scientists.

A prospective cohort study of renal function and bone turnover in adults with hepatitis B virus (HBV)-HIV co-infection with high prevalence of tenofovir-based antiretroviral therapy use.

OBJECTIVE: Tenofovir disoproxil fumarate (TDF) is a common component of antiretroviral therapy in hepatitis B virus (HBV)-HIV co-infected adults but few studies have evaluated worsening renal function and bone turnover, known effects of TDF. METHODS: Adults from eight North American sites were enrolled in this cohort study. Research assessments were conducted at entry and every 24 weeks for ≤192 weeks. Bone markers were tested at baseline, week 96 and week 192 from stored serum. We evaluated changes in markers of renal function and bone turnover over time and potential contributing factors. RESULTS: A total of 115 patients were prospectively followed; median age 49 years, 91% male and 52% non-Hispanic Black. Duration of HIV was 20.5 years. TDF use ranged from 80% to 92% throughout follow-up. Estimated glomerular filtration rate (eGFR) (ml/min/1.73m2 ) decreased from 87.1 to 79.9 over 192 weeks (p < 0.001); however, the prevalence of eGFR <60 ml/min/1.73m2 did not appear to differ over time (always <16%; p = 0.43). From baseline to week 192, procollagen type I N-terminal propeptide (P1NP) (146.7 to 130.5 ng/ml; p = 0.001), osteocalcin (14.4 to 10.2 ng/ml; p < 0.001) and C-terminal telopeptides of type I collagen (CTX-1) (373 to 273 pg/ml; p < 0.001) decreased. Younger age, male sex and overweight/obesity versus normal weight predicted a decrease in eGRF. Black race, healthy weight versus underweight, advanced fibrosis, undetectable HBV DNA, and lower parathyroid hormone level predicted worsening bone turnover. CONCLUSION: In this HBV-HIV cohort with high prevalence of TDF use, several biomarkers of renal function and bone turnover indicated worsening status over approximately 4 years, highlighting the importance of clinical awareness in co-infected adults.

DNA Methylation Research in Autologous Hematopoietic Stem Cell Transplant Population.

Despite increased sophistication in DNA methylation (DNAm) measurement and methods, conducting studies in specific populations such as the hematopoietic stem cell transplant (HCT) population, presents unique challenges and study design considerations. In this article, we explain the motivation for investigating DNAm in the HCT population, highlighting important study design features and key findings in a longitudinal prospective pilot study of DNAm in 32 patients undergoing autologous HCT in Central Virginia, USA. We also discuss limitations and challenges to generating robust results. We observed that HCT does not prevent high-quality DNA from being extracted from whole blood for DNAm research and that longitudinal prospective studies that span pre- and 2-months post-HCT are feasible. Critically, we did not observe significant impacts of cancer diagnosis, time since transplant, age, or chromosomal sex on overall DNAm data dimensionality. These observations demonstrate that while extreme care is required to ensure generalizable, accurate, and interpretable results, researchers should not avoid HCT-DNAm research simply for fear that the transplant procedure or presence of a cancer diagnosis will prevent meaningful conclusions from being drawn. DNAm is an attractive biomarker that is understudied in patients undergoing HCT and needs to expand to improve precise prediction of HCT outcomes.

DNA Methylation Changes in Autologous Hematopoietic Stem Cell Transplant Patients.

BACKGROUND: Blood cancers may be potentially cured with hematopoietic stem cell transplantation (HCT); however, standard pre-assessments for transplant eligibility do not capture all contributing factors for transplant outcomes. Epigenetic biomarkers predict outcomes in various diseases. This pilot study aims to explore epigenetic changes (epigenetic age and differentially methylated genes) in patients before and after autologous HCT, that can serve as potential biomarkers to better predict HCT outcomes. METHODS: This study used a prospective longitudinal study design to compare genome wide DNA methylation changes in 36 autologous HCT eligible patients recruited from the Cellular Immunotherapies and Transplant clinic at a designated National Cancer Center. RESULTS: Genome-wide DNA methylation, measured by the Illumina Infinium Human Methylation 850K BeadChip, showed a significant difference in DNA methylation patterns post-HCT compared to pre-HCT. Compared to baseline levels of DNA methylation pre-HCT, 3358 CpG sites were hypo-methylated and 3687 were hyper-methylated. Identified differentially methylated positions overlapped with genes involved in hematopoiesis, blood cancers, inflammation and immune responses. Enrichment analyses showed significant alterations in biological processes such as immune response and cell structure organization, however no significant pathways were noted. Though participants had an advanced epigenetic age compared to chronologic age before and after HCT, both epigenetic age and accelerated age decreased post-HCT. CONCLUSION: Epigenetic changes, both in epigenetic age and differentially methylated genes were observed in autologous HCT recipients, and should be explored as biomarkers to predict transplant outcomes after autologous HCT in larger, longitudinal studies.

Extracellular Vesicle MicroRNA in Malignant Pleural Effusion.

Lung and breast cancer are the two most common causes of malignant pleural effusion (MPE). MPE diagnosis plays a crucial role in determining staging and therapeutic interventions in these cancers. However, our understanding of the pathogenesis and progression of MPE at the molecular level is limited. Extracellular Vesicles (EVs) and their contents, including microRNAs (miRNAs), can be isolated from all bodily fluids, including pleural fluid. This study aims to compare EV-miRNA patterns of expression in MPE caused by breast (BA-MPE) and lung (LA-MPE) adenocarcinomas compared to the control group of heart-failure-induced effusions (HF-PE). We conducted an analysis of 24 pleural fluid samples (8 LA-MPE, 8 BA-MPE, and 8 HF-PE). Using NanoString technology, we profiled miRNAs within EVs isolated from 12 cases. Bioinformatic analysis demonstrated differential expression of miR-1246 in the MPE group vs. HF-PE group and miR-150-5p and miR-1246 in the BA-MPE vs. LA-MPE group, respectively. This difference was demonstrated and validated in an independent cohort using real-time PCR (RT-PCR). miRNA-1246 demonstrated 4-fold increased expression (OR: 3.87, 95% CI: 0.43, 35) in the MPE vs. HF-PE group, resulting in an area under the curve of 0.80 (95% CI: 0.60, 0.99). The highest accuracy for differentiating MPE vs. HF-PE was seen with a combination of miRNAs compared to each miRNA alone. Consistent with prior studies, this study demonstrates dysregulation of specific EV-based miRNAs in breast and lung cancer; pleural fluid provides direct access for the analysis of these EV-miRNAs as biomarkers and potential targets and may provide insight into the underlying pathogenesis of tumor progression. These findings should be explored in large prospective studies.

Factors Affecting Quality of Life in Patients Receiving Autologous Hematopoietic Stem Cell Transplantation.

BACKGROUND: Hematopoietic stem cell transplant (HSCT) is a potentially curative treatment for hematologic malignancies, with 22 000 HSCTs performed annually in the United States. However, decreased quality of life (QoL) is a frequent and concerning state reported by HSCT recipients. OBJECTIVES: We sought to determine if measurements of frailty and cognitive impairment were associated with fatigue and QoL in adult HSCT recipients after autologous HSCT. METHODS: Using a longitudinal study design, 32 participants 18 years or older receiving autologous HSCT were recruited from a bone marrow transplant clinic. Each participant completed 2 visits: pre-HSCT and post-HSCT. At each visit, participants completed assessment tools to measure frailty, cognitive impairment, fatigue, and QoL (assesses physical, social/family, emotional, functional, and transplant-related well-being). RESULTS: Participants with increased fatigue scores reported decreased QoL pre- and post-HSCT. Participants with increased frailty showed decreased functional well-being before HSCT and showed correlations with decreased physical, social, and transplant-related well-being post-HSCT. As expected, fatigued participants also showed increased frailty post-HSCT. Participants showed significant changes in physical well-being and fatigue between pre-HSCT and post-HSCT visits. CONCLUSION: Data analyses from this pilot study show significant correlations between subsets of QoL with fatigue and frailty in autologous HSCT participants pre- and post-HSCT. IMPLICATIONS FOR PRACTICE: Understanding the impact of frailty on fatigue and QoL in HSCT recipients is critical to assist nurses in initiating educational and behavioral interventions to help mitigate the effects of HSCT.

Frailty in Patients With Hematologic Malignancies and Those Undergoing Transplantation: A Scoping Review.

PROBLEM IDENTIFICATION: Although frailty is an important parameter in treatment planning and in predicting prognosis and overall survival among patients with hematologic malignancies and recipients of hematopoietic stem cell transplantation, frailty assessment tools are not standardized in clinical care settings. The purpose of this article is to provide an overview of the literature on frailty assessment tools in these patient populations. LITERATURE SEARCH: A systematic search of CINAHL®, Embase®, MEDLINE®, PubMed®, and Web of Science was performed using keywords and controlled vocabulary for the concepts "bone marrow transplants," "hematologic neoplasms," and "frailty." DATA EVALUATION: Extracted data included study type, diagnosis, transplantation status, frailty tools used, and outcome measures. SYNTHESIS: A systematic search resulted in 24 studies that met the inclusion criteria. There were significant differences in how various groups define and assess frailty. IMPLICATIONS FOR PRACTICE: Addressing the lack of standardized frailty assessments will assist healthcare providers to routinely integrate frailty measures in clinical assessments to identify those at risk for poor outcomes, improving personalized care.

Exploring Associations Between Metabolites and Symptoms of Fatigue, Depression and Pain in Women With Fibromyalgia.

Fibromyalgia (FM) is a chronic noncommunicable disorder characterized by a constellation of symptoms that include fatigue, depression and chronic pain. FM affects 2%-8% of the U.S. population, 2% of the global population, with 61%-90% of FM diagnoses attributed to women. Key causal factors leading to the development and severity of FM-related symptoms have not yet been identified. The purpose of this article is to report relationships among identified metabolites and levels of fatigue, depression, pain severity, and pain interference in a sample of 20 women with FM. In this secondary analysis, we conducted global metabolomic analysis and examined the data for relationships of metabolite levels with self-reported symptoms of fatigue, depression, pain severity, and pain interference. Results revealed six metabolites (6-deoxy-hexose; pantothenic acid; ergothioneine; l-carnitine; n-acetylserotonin; butyrobetaine) and their associated metabolic pathways such as carnitine synthesis, lipid oxidation, tryptophan metabolism, beta-alanine metabolism and pantothenic and Coenzyme-A biosynthesis that were either positively or inversely related to pain severity, pain interference, or both. The preliminary data presented suggest that metabolites representing energy, amino acid, or lipid classification may be associated with pain symptom severity and interference in women with FM. Future work will confirm these findings in a large, comparative cohort, targeting metabolites and metabolite pathways to better understand the relationships of metabolites and symptomology.

A mindful yoga intervention for children with severe asthma: A pilot study.

INTRODUCTION: Children with severe asthma may benefit from non-pharmacological approaches to symptom management, yet little is known regarding the impact of mind-body approaches such as mindful yoga in this population. This pilot study examined the tolerability, feasibility, acceptability and immediate effects of a mindful yoga intervention in children with severe asthma. METHOD: Fifteen children ages 7-11 with severe asthma participated in a single mindful yoga session, followed by semi-structured interviews with the child and caregiver. Vital signs and pulmonary function tests were collected pre- and post-intervention. RESULTS: All children reported positive experiences and caregivers were generally supportive of their participation. One child experienced self-limited bronchoconstriction with asthma symptoms. There was no significant change in lung function or vital signs after the mindful yoga session. DISCUSSION: Our results warrant additional larger studies to evaluate the safety and benefits of mindful yoga in children with severe asthma.

Shared mechanisms for cognitive impairment and physical frailty: A model for complex systems.

INTRODUCTION: We describe findings from a large study that provide empirical support for the emerging construct of cognitive frailty and put forth a theoretical framework that may advance the future study of complex aging conditions. While cognitive impairment and physical frailty have long been studied as separate constructs, recent studies suggest they share common etiologies. We aimed to create a population predictive model to gain an understanding of the underlying biological mechanisms for the relationship between physical frailty and cognitive impairment. METHODS: Data were obtained from the longitudinal "Invecchaiare in Chianti" (Aging in Chianti, InCHIANTI Study) with a representative sample (n = 1453) of older adults from two small towns in Tuscany, Italy. Our previous work informed the candidate 132 single nucleotide polymorphisms (SNPs) and 155 protein biomarkers we tested in association with clinical outcomes using a tree boosting, machine learning (ML) technique for supervised learning analysis. RESULTS: We developed two highly accurate predictive models, with a Model I area under the curve (AUC) of 0.88 (95% confidence interval [CI] 0.83-0.90) and a Model II AUC of 0.86 (95% CI 0.80-0.90). These models indicate cognitive frailty is driven by dysregulation across multiple cellular processes including genetic alterations, nutrient and lipid metabolism, and elevated levels of circulating pro-inflammatory proteins. DISCUSSION: While our results establish a foundation for understanding the underlying biological mechanisms for the relationship between cognitive decline and physical frailty, further examination of the molecular pathways associated with our predictive biomarkers is warranted. Our framework is in alignment with other proposed biological underpinnings of Alzheimer's disease such as genetic alterations, immune system dysfunction, and neuroinflammation.

The Obesity Paradox in Sepsis: A Theoretical Framework.

Sepsis is a life-threatening syndrome that occurs in response to a severe infection. In recent years, the understanding of the pathobiology of sepsis has been refined, with research describing an altered host response as the underlying cause. Survivors of sepsis often have long hospital stays and suffer from subsequent frailty and long-term health consequences. Predicting attributes of sepsis survivors remains challenging; however, an obesity paradox exists, wherein obese individuals survive sepsis at higher rates than their normal-weight counterparts. We present a model that describes the relationships between sepsis and obesity, focusing on inflammation as a shared pathway for dysregulation in obese and healthy-weight adults. Understanding the interaction of these complex variables is an important first step toward developing interventions and treatments to augment sepsis survival.

Vitamin C Intravenous Treatment In the Setting of Atrial Fibrillation Ablation: Results From the Randomized, Double-Blinded, Placebo-Controlled CITRIS-AF Pilot Study.

Background Catheter ablation is an effective treatment for atrial fibrillation (AF), but high levels of post-procedure inflammation predict adverse clinical events. Ascorbic acid (AA) has shown promise in reducing inflammation but is untested in this population. We sought to test the feasibility, safety, and preliminary effects on inflammatory biomarkers in the CITRIS-AF (Vitamin C Intravenous Treatment In the Setting of Atrial Fibrillation Ablation) pilot study. Methods and Results Patients scheduled to undergo AF ablation (N=20) were randomized 1:1 to double-blinded treatment with AA (200 mg/kg divided over 24 hours) or placebo. C-reactive protein and interleukin-6 levels were obtained before the first infusion and repeated at 24 hours and 30 days. Pain levels within 24 hours and early recurrence of AF within 90 days were recorded. Median and interquartile range were aged 63 (56-70) years, 13 (65%) men, and 18 (90%) white. Baseline data were similar between the 2 groups except ejection fraction. Baseline C-reactive protein levels were 2.56 (1.47-5.87) mg/L and similar between groups (P=0.48). Change in C-reactive protein from baseline to 24 hours was +10.79 (+6.56-23.19) mg/L in the placebo group and +3.01 (+0.40-5.43) mg/L in the AA group (P=0.02). Conversely, change in interleukin-6 was numerically higher in the AA group, though not statistically significant (P=0.32). One patient in each arm developed pericarditis; no adverse events related to the infusions were seen. There were no significant differences between aggregated post-procedure pain levels within 24 hours or early recurrence of AF (both P>0.05). Conclusions High-dose AA is safe and well tolerated at the time of AF ablation and may be associated with a blunted rise in C-reactive protein, although consistent findings were not seen in interleukin-6 levels. Further studies are needed to validate these findings and explore the potential benefit in improving clinically relevant outcomes. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT03148236.

Obesity and 1-Year Mortality in Adults After Sepsis: A Systematic Review.

PURPOSE: In recent years, researchers have noted an "obesity paradox," where individuals with obesity survive sepsis at higher rates than their nonobese counterparts. This systematic review summarizes the literature on studies examining the association between obesity and 1-year mortality among patients admitted with sepsis, severe sepsis, or septic shock. MATERIALS AND METHODS: Using a comprehensive search strategy, a systematic review was conducted to identify studies examining the association of obesity and sepsis mortality. PubMed, Cumulative Index of Nursing and Allied Health Literature, and Elton B. Stephens Company host databases were searched for the terms sepsis, obesity, mortality, and adult. RESULTS: The initial search identified 189 studies, 9 of which met inclusion criteria. Of these, four provided evidence that obese or very obese patients with sepsis have lower mortality than nonobese patients. Methodologic differences in the remaining five studies, which reported conflicting results, limit generalizability. CONCLUSION: This systematic review on the association of obesity and sepsis mortality found three studies that demonstrated lower sepsis mortality among obese patients in the first 30 days and one showing that this protective effect extends up to 1 year. Given the increased number of patients surviving sepsis, it is important to consider long-term mortality and further describe the variables associated with increased survival.

Metabolomic Differentials in Women With and Without Fibromyalgia.

A nontargeted plasma metabolomic analysis was conducted to compare differentially expressed metabolites in women with and without fibromyalgia (FM) using data and samples collected from two parent studies in women with FM (n = 20) and comparative data collected from newly recruited age-matched women (n = 20). Blood plasma samples were analyzed for metabolite content using liquid chromatography mass spectrometry. Consolidation of positive and negative ion mode metabolomics data with fold change (>2 or <0.5) and variable importance of projection scores ≥1 revealed statistically significant metabolites comparing samples from women with and without FM. Metabolite profiles in patients with FM differed from the comparison group in energy, lipid and amino acid metabolites reflecting heightened oxidative stress, inflammation, and tryptophan degradation in patients with FM. Study results may contribute to further identification of unique metabolomic profiles enhancing understanding of the pathophysiology of FM and for the development of effective therapeutic options.

Breast tumor DNA methylation patterns associated with smoking in the Carolina Breast Cancer Study.

PURPOSE: Tobacco smoking is a risk factor in several cancers, yet its roles as a putative etiologic exposure or poor prognostic factor in breast cancer are less clear. Altered DNA methylation contributes to breast cancer development and may provide a mechanistic link between smoking and gene expression changes leading to cancer development or progression. METHODS: Using a cancer-focused array, we examined methylation at 933 CpGs in 517 invasive breast tumors in the Carolina Breast Cancer Study to determine whether methylation patterns differ by exposure to tobacco smoke. Multivariable generalized linear regression models were used to compare tumor methylation profiles between smokers and never smokers, overall, or stratified on hormone receptor (HR) status. RESULTS: Modest differences in CpG methylation were detected at p < 0.05 in breast tumors from current or ever smokers compared with never smokers. In stratified analyses, HR- tumors from smokers exhibited primarily hypomethylation compared with tumors from never smokers; hypomethylation was similarly detected within the more homogeneous basal-like subtype. Most current smoking-associated CpG loci exhibited methylation levels in former smokers that were intermediate between those in current and never smokers and exhibited progressive changes in methylation with increasing duration of smoking. Among former smokers, restoration of methylation toward baseline (never smoking) levels was observed with increasing time since quitting. Moreover, smoking-related hypermethylation was stronger in HR+ breast tumors from blacks than in whites. CONCLUSIONS: Our results suggest that breast tumor methylation patterns differ with tobacco smoke exposure; however, additional studies are needed to confirm these findings.

Waking up dormant tumor suppressor genes with zinc fingers, TALEs and the CRISPR/dCas9 system.

The aberrant epigenetic silencing of tumor suppressor genes (TSGs) plays a major role during carcinogenesis and regaining these dormant functions by engineering of sequence-specific epigenome editing tools offers a unique opportunity for targeted therapies. However, effectively normalizing the expression and regaining tumor suppressive functions of silenced TSGs by artificial transcription factors (ATFs) still remains a major challenge. Herein we describe novel combinatorial strategies for the potent reactivation of two class II TSGs, MASPIN and REPRIMO, in cell lines with varying epigenetic states, using the CRISPR/dCas9 associated system linked to a panel of effector domains (VP64, p300, VPR and SAM complex), as well as with protein-based ATFs, Zinc Fingers and TALEs. We found that co-delivery of multiple effector domains using a combination of CRISPR/dCas9 and TALEs or SAM complex maximized activation in highly methylated promoters. In particular, CRISPR/dCas9 VPR with SAM upregulated MASPIN mRNA (22,145-fold change) in H157 lung cancer cells, with accompanying re-expression of MASPIN protein, which led to a concomitant inhibition of cell proliferation and induction of apoptotic cell death. Consistently, CRISPR/dCas9 VP64 with SAM upregulated REPRIMO (680-fold change), which led to phenotypic reprogramming in AGS gastric cancer cells. Altogether, our results outlined novel sequence-specific, combinatorial epigenome editing approaches to reactivate highly methylated TSGs as a promising therapy for cancer and other diseases.

Racial variation in breast tumor promoter methylation in the Carolina Breast Cancer Study.

BACKGROUND: African American (AA) women are diagnosed with more advanced breast cancers and have worse survival than white women, but a comprehensive understanding of the basis for this disparity remains unclear. Analysis of DNA methylation, an epigenetic mechanism that can regulate gene expression, could help to explain racial differences in breast tumor clinical biology and outcomes. METHODS: DNA methylation was evaluated at 1,287 CpGs in the promoters of cancer-related genes in 517 breast tumors of AA (n = 216) or non-AA (n = 301) cases in the Carolina Breast Cancer Study (CBCS). RESULTS: Multivariable linear regression analysis of all tumors, controlling for age, menopausal status, stage, intrinsic subtype, and multiple comparisons [false discovery rate (FDR)], identified seven CpG probes that showed significant (adjusted P < 0.05) differential methylation between AAs and non-AAs. Stratified analyses detected an additional four CpG probes differing by race within hormone receptor-negative (HR(-)) tumors. Genes differentially methylated by race included DSC2, KCNK4, GSTM1, AXL, DNAJC15, HBII-52, TUSC3, and TES; the methylation state of several of these genes may be associated with worse survival in AAs. TCGA breast tumor data confirmed the differential methylation by race and negative correlations with expression for most of these genes. Several loci also showed racial differences in methylation in peripheral blood leukocytes (PBL) from CBCS cases, indicating that these variations were not necessarily tumor-specific. CONCLUSIONS: Racial differences in the methylation of cancer-related genes are detectable in both tumors and PBLs from breast cancer cases. IMPACT: Epigenetic variation could contribute to differences in breast tumor development and outcomes between AAs and non-AAs.

Body mass index is associated with gene methylation in estrogen receptor-positive breast tumors.

BACKGROUND: Although obesity is associated with breast cancer incidence and prognosis, the underlying mechanisms are poorly understood. Identification of obesity-associated epigenetic changes in breast tissue may advance mechanistic understanding of breast cancer initiation and progression. The goal of this study, therefore, was to investigate associations between obesity and gene methylation in breast tumors. METHODS: Using the Illumina GoldenGate Cancer I Panel, we estimated the association between body mass index (BMI) and gene methylation in 345 breast tumor samples from phase I of the Carolina Breast Cancer Study, a population-based case-control study. Multivariable linear regression was used to identify sites that were differentially methylated by BMI. Stratification by tumor estrogen receptor (ER) status was also conducted. RESULTS: In the majority of the 935 probes analyzed (87%), the average beta value increased with obesity (BMI ≥ 30). Obesity was significantly associated with differential methylation (FDR q < 0.05) in just two gene loci in breast tumor tissue overall and in 21 loci among ER-positive tumors. Obesity was associated with methylation of genes that function in immune response, cell growth, and DNA repair. CONCLUSIONS: Obesity is associated with altered methylation overall, and with hypermethylation among ER-positive tumors in particular, suggesting that obesity may influence the methylation of genes with known relevance to cancer. Some of these differences in methylation by obese status may influence levels of gene expression within breast cells. IMPACT: If our results are validated, obesity-associated methylation sites could serve as targets for prevention and treatment research. Cancer Epidemiol Biomarkers Prev; 24(3); 580-6. ©2015 AACR.

Deconstructing breast cancer heterogeneity: clinical implications for women with Basal-like tumors.

PURPOSE/OBJECTIVES: To compare and contrast the molecular and environmental factors contributing to basal-like breast cancer and highlight the clinical implications for women with this phenotype. DATA SOURCES: CINAHL® and PubMed databases, journals, and citation indices were searched using the key word basal-like in combination with breast cancer, epigenetic, treatment, subtype, risk factor, and BRCA1 to synthesize the literature on the multiple underpinnings of basal-like breast cancer. DATA SYNTHESIS: Research findings related to the molecular foundation of basal-like breast cancer were integrated with knowledge of nongenetic contributing risk factors. Approved therapies and those under development were summarized with the goal of improving understanding for research and practice. CONCLUSIONS: Of the five subtypes of breast cancer, the basal-like subtype has the shortest survival and poorest prognosis. The development of gene expression assays with epigenetic studies has enabled reliable identification of the basal-like subtype and has shed light on novel therapeutic possibilities. Clinical trials for basal-like breast cancer are underway, and the potential for individualized treatments for women with this subtype show promise. IMPLICATIONS FOR NURSING: The main difficulties with basal-like breast cancer are its aggressive course, treatment refractory nature, and complex biology, all of which pose real challenges for clinical management and patient education. Oncology nurses play a pivotal role in providing holistic care and patient support. Therefore, nurses must understand the complexity of the clinical presentation and the underlying biology of this cancer subtype.