Faculty Bibliography
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314
Lymphatic and Angiogenic Candidate Genes Predict the Development of Secondary Lymphedema following Breast Cancer Surgery
The purposes of this study were to evaluate for differences in phenotypic and genotypic characteristics in women who did and did not develop lymphedema (LE) following breast cancer treatment. Breast cancer patients completed a number of self-report questionnaires. LE was evaluated using bioimpedance spectroscopy. Genotyping was done using a custom genotyping array. No differences were found between patients with (n = 155) and without LE (n = 387) for the majority of the demographic and clinical characteristics. Patients with LE had a significantly higher body mass index, more advanced disease and a higher number of lymph nodes removed. Genetic associations were identified for four genes (i.e., lymphocyte cytosolic protein 2 (rs315721), neuropilin-2 (rs849530), protein tyrosine kinase (rs158689), vascular cell adhesion molecule 1 (rs3176861)) and three haplotypes (i.e., Forkhead box protein C2 (haplotype A03), neuropilin-2 (haplotype F03), vascular endothelial growth factor-C (haplotype B03)) involved in lymphangiogensis and angiogenesis. These genetic associations suggest a role for a number of lymphatic and angiogenic genes in the development of LE following breast cancer treatment.
PMCID:3629060
PMID: 23613720
ISSN: 1932-6203
CID: 316182
Identification of patient subgroups and risk factors for persistent breast pain following breast cancer surgery
Study purposes were to determine the prevalence of persistent pain in the breast; characterize distinct persistent pain classes using growth mixture modeling; and evaluate for differences among these pain classes in demographic, preoperative, intraoperative, and postoperative characteristics. In addition, differences in the severity of common symptoms and quality of life outcomes measured prior to surgery, among the pain classes, were evaluated. Patients (n = 398) were recruited prior to surgery and followed for 6 months. Using growth mixture modeling, patients were classified into no (31.7%), mild (43.4%), moderate (13.3%), and severe (11.6%) pain groups based on ratings of worst breast pain. Differences in a number of demographic, preoperative, intraoperative, and postoperative characteristics differentiated among the pain classes. In addition, patients in the moderate and severe pain classes reported higher preoperative levels of depression, anxiety, and sleep disturbance than the no pain class. Findings suggest that approximately 25% of women experience significant and persistent levels of breast pain in the first 6 months following breast cancer surgery. PERSPECTIVE: Persistent pain is a significant problem for 25% of women following surgery for breast cancer. Severe breast pain is associated with clinically meaningful decrements in functional status and quality of life.
PMCID:3511823
PMID: 23182226
ISSN: 1526-5900
CID: 202502
Gene-environment interactions in cardiovascular disease
BACKGROUND: Historically, models to describe disease were exclusively nature-based or nurture-based. Current theoretical models for complex conditions such as cardiovascular disease acknowledge the importance of both biologic and non-biologic contributors to disease. A critical feature is the occurrence of interactions between numerous risk factors for disease. The interaction between genetic (i.e., biologic, nature) and environmental (i.e. non-biologic, nurture) causes of disease is an important mechanism for understanding both the etiology and public health impact of cardiovascular disease. OBJECTIVES: The purpose of this paper is to describe theoretical underpinnings of gene-environment interactions, models of interaction, methods for studying gene-environment interactions, and the related concept of interactions between epigenetic mechanisms and the environment. DISCUSSION: Advances in methods for measurement of genetic predictors of disease have enabled an increasingly comprehensive understanding of the causes of disease. In order to fully describe the effects of genetic predictors of disease, it is necessary to place genetic predictors within the context of known environmental risk factors. The additive or multiplicative effect of the interaction between genetic and environmental risk factors is often greater than the contribution of either risk factor alone.
PMCID:3197961
PMID: 21684212
ISSN: 1873-1953
CID: 1563812
Erratum: Mouse and human strategies identify PTPN14 as a modifier of angiogenesis and hereditary haemorrhagic telangiectasia (Nature Communications (2012) 3 (616) DOI: 10.1038/ncomms1633) [Correction]
SCOPUS:84869470463
ISSN: 2041-1723
CID: 2803912
A single-nucleotide polymorphism in CYP2B6 leads to >3-fold increases in efavirenz concentrations in plasma and hair among HIV-infected women
BACKGROUND: Efavirenz exhibits marked interindividual variability in plasma levels and toxicities. Prior pharmacogenetic studies usually measure exposure via single plasma levels, examine limited numbers of polymorphisms, and rarely model multiple contributors. We analyzed numerous genetic and nongenetic factors impacting short-term and long-term exposure in a large heterogeneous population of human immunodeficiency virus (HIV)-infected women. METHODS: We performed 24-hour intensive pharmacokinetic studies in 111 women receiving efavirenz under actual-use conditions and calculated the area-under-the-concentration-time curve (AUC) to assess short-term exposure; the efavirenz concentration in hair was measured to estimate long-term exposure. A total of 182 single-nucleotide polymorphisms (SNPs) and 45 haplotypes in 9 genes were analyzed in relationship to exposure by use of multivariate models that included a number of nongenetic factors. RESULTS: Efavirenz AUCs increased 1.26-fold per doubling of the alanine aminotransferase level and 1.23-fold with orange and/or orange juice consumption. Individuals with the CYP2B6 516TT genotype displayed 3.5-fold increases in AUCs and 3.2-fold increases in hair concentrations, compared with individuals with the TG/GG genotype. Another SNP in CYP2B6 (983TT) and a p-glycoprotein haplotype affected AUCs without substantially altering long-term exposure. CONCLUSIONS: This comprehensive pharmacogenomics study showed that individuals with the CYP2B6 516TT genotype displayed >3-fold increases in both short-term and long-term efavirenz exposure, signifying durable effects. Pharmacogenetic testing combined with monitoring of hair levels may improve efavirenz outcomes and reduce toxicities.
PMCID:3466997
PMID: 22927450
ISSN: 1537-6613
CID: 1563822
Lower serum hepcidin and greater parenchymal iron in nonalcoholic fatty liver disease patients with C282Y HFE mutations
UNLABELLED:Hepcidin regulation is linked to both iron and inflammatory signals and may influence iron loading in nonalcoholic steatohepatitis (NASH). The aim of this study was to examine the relationships among HFE genotype, serum hepcidin level, hepatic iron deposition, and histology in nonalcoholic fatty liver disease (NAFLD). Single-nucleotide polymorphism genotyping for C282Y (rs1800562) and H63D (rs1799945) HFE mutations was performed in 786 adult subjects in the NASH Clinical Research Network (CRN). Clinical, histologic, and laboratory data were compared using nonparametric statistics and multivariate logistic regression. NAFLD patients with C282Y, but not H63D mutations, had lower median serum hepcidin levels (57 versus 65 ng/mL; P = 0.01) and higher mean hepatocellular (HC) iron grades (0.59 versus 0.28; P < 0.001), compared to wild-type (WT) subjects. Subjects with hepatic iron deposition had higher serum hepcidin levels than subjects without iron for all HFE genotypes (P < 0.0001). Hepcidin levels were highest among patients with mixed HC/reticuloendothelial system cell (RES) iron deposition. H63D mutations were associated with higher steatosis grades and NAFLD activity scores (odds ratio [OR], ≥1.4; 95% confidence interval [CI]: >1.0, ≤2.5; P ≤ 0.041), compared to WT, but not with either HC or RES iron. NAFLD patients with C282Y mutations had less ballooning or NASH (OR, ≤0.62; 95% CI: >0.39, <0.94; P ≤ 0.024), compared to WT subjects. CONCLUSIONS/CONCLUSIONS:The presence of C282Y mutations in patients with NAFLD is associated with greater HC iron deposition and decreased serum hepcidin levels, and there is a positive relationship between hepatic iron stores and serum hepcidin level across all HFE genotypes. These data suggest that body iron stores are the major determinant of hepcidin regulation in NAFLD, regardless of HFE genotype. A potential role for H63D mutations in NAFLD pathogenesis is possible through iron-independent mechanisms.
PMCID:3462887
PMID: 22611049
ISSN: 0270-9139
CID: 2807682
Underlying genetic structure impacts the association between CYP2B6 polymorphisms and response to efavirenz and nevirapine
OBJECTIVE: CYP2B6 variation predicts pharmacokinetic characteristics of its substrates. Consideration for underlying genetic structure is critical to protect against spurious associations with the highly polymorphic CYP2B6 gene. DESIGN: The effect of CYP2B6 variation on response to its substrates, nonnucleoside reverse transcriptase inhibitors (NNRTIs), was explored in the Women's Interagency HIV Study. METHODS: Five putative functional polymorphisms were tested for associations with virologic suppression within 1 year after NNRTI initiation in women naive to antiretroviral agents (n = 91). Principal components were generated to control for population substructure. Logistic regression was used to test the joint effect of rs3745274 and rs28399499, which together indicate slow, intermediate, and extensive metabolizers. RESULTS: Rs3745274 was significantly associated with virologic suppression [odds ratio = 3.61, 95% confidence interval (CI) 1.16-11.22, P trend = 0.03]; the remaining polymorphisms tested were not significantly associated with response. Women classified as intermediate and slow metabolizers were 2.90 (95% CI 0.79-12.28) and 13.44 (95% CI 1.66 to infinity) times as likely to achieve virologic suppression compared to extensive metabolizers after adjustment for principal components (P trend = 0.005). Failure to control for genetic ancestry resulted in substantial confounding of the relationship between the metabolizer phenotype and treatment response. CONCLUSION: The CYP2B6 metabolizer phenotype was significantly associated with virologic response to NNRTIs; this relationship would have been masked by simple adjustment for self-reported ethnicity. Given the appreciable genetic heterogeneity that exists within self-reported ethnicity, these results exemplify the importance of characterizing underlying genetic structure in pharmacogenetic studies. Further follow-up of the CYP2B6 metabolizer phenotype is warranted, given the potential clinical importance of this finding.
PMCID:3940150
PMID: 22951632
ISSN: 1473-5571
CID: 1563832
Trajectories and predictors of symptom occurrence, severity, and distress in prostate cancer patients undergoing radiation therapy
CONTEXT: Radiation therapy (RT) is a common treatment for prostate cancer. Despite available research, prostate cancer patients report that information about side effects is their most important unmet need. Additional research is needed that focuses on specific dimensions of the patient's symptom experience. OBJECTIVES: The study's purposes were to evaluate the trajectories of occurrence, severity, and distress of the six most prevalent symptoms reported by patients undergoing RT for prostate cancer and the effects of selected demographic and clinical characteristics on these trajectories. METHODS: Patients completed the Memorial Symptom Assessment Scale 11 times before, during, and after RT. For problems with urination, pain, lack of energy, feeling drowsy, difficulty sleeping, and diarrhea, the trajectories of occurrence, severity, and distress were evaluated using multilevel generalized linear models. RESULTS: Across all three dimensions, pain, lack of energy, feeling drowsy, and difficulty sleeping followed a decreasing linear trend. Problems with urination and diarrhea demonstrated more complex patterns of change over time. CONCLUSION: Although longitudinal data on pain, lack of energy, feeling drowsy, and difficulty sleeping are limited, they are highly prevalent symptoms in these patients. In addition, diarrhea becomes a significant problem for these patients over the course of RT. A number of demographic and clinical characteristics affect the trajectories of these common symptoms differentially.
PMCID:3463773
PMID: 22771128
ISSN: 1873-6513
CID: 1563842
Identification of distinct subgroups of breast cancer patients based on self-reported changes in sleep disturbance
PURPOSE: The purposes of this study were to identify distinct subgroups of patients based on self-reported sleep disturbance prior to through 6 months after breast cancer surgery and evaluate for differences in demographic, clinical, and symptom characteristics among these latent classes. METHODS: Women (n = 398) who underwent unilateral breast cancer surgery were enrolled prior to surgery. Patients completed measures of functional status, sleep disturbance (i.e., General Sleep Disturbance Scale (GSDS); higher scores indicate higher levels of sleep disturbance), fatigue, attentional fatigue, depressive symptoms, and anxiety prior to surgery and monthly for 6 months. RESULTS: Three distinct classes of sleep disturbance trajectories were identified using growth mixture modeling. The high sustained class (55.0%) had high and the low sustained class (39.7%) had low GSDS scores prior to surgery that persisted for 6 months. The decreasing class (5.3%) had high GSDS score prior to surgery that decreased over time. Women in the high sustained class were significantly younger, had more comorbidity and poorer function, and were more likely to report hot flashes compared to the low sustained class. More women who underwent mastectomy or breast reconstruction were in the decreasing class. Decreasing and high sustained classes reported higher levels of physical fatigue, attentional fatigue, depressive symptoms, and anxiety compared to the low sustained class. CONCLUSIONS: A high percentage of women has significant sleep disturbance prior to surgery that persists during subsequent treatments (i.e., radiation therapy and chemotherapy). Clinicians need to perform routine assessments and initiate appropriate interventions to improve sleep prior to and following surgery.
PMID: 22290719
ISSN: 1433-7339
CID: 1563852
Determination of cutpoints for low and high number of symptoms in patients with advanced cancer
While patients with advanced cancer experience a wide range of symptoms, no work has been done to determine an optimal cutpoint for a low versus a high number of symptoms. Analytic approaches that established clinically meaningful cutpoints for the severity of cancer pain and fatigue provided the foundation for this study. The purpose of this study was to determine the optimal cutpoint for low and high numbers of symptoms using a range of potential cutpoints and to determine if those cutpoints distinguished between the two symptom groups on demographic and clinical characteristics and depression, anxiety, and quality of life (QOL). Patients with advanced cancer (n=110) completed a symptom assessment scale, and measures of depression, anxiety, and QOL. Combinations of cutpoints were tested to yield one- and two-cutpoint solutions. Using analysis of variance for QOL scores, the F-ratio that indicated the highest between-group difference was determined to be the optimal cutpoint between low and high number of symptoms. A cutpoint of
PMCID:3422053
PMID: 22853731
ISSN: 1557-7740
CID: 1563862
