Bradley E. Aouizerat

Abstract

We previously demonstrated the role of a phospholipid transfer protein (PLTP) gene variation (rs2294213) in determining levels of high-density lipoprotein cholesterol (HDL-C) in hypoalphalipoproteinemia (HypoA). We have now explored the role of PLTP in hyperalphalipoproteinemia (HyperA). The human PLTP gene was screened for sequence anomalies by DNA melting in 107 subjects with HyperA. The association with plasma lipoprotein levels was evaluated. We detected 7 sequence variations: 1 previously reported variation (rs2294213) and 5 novel mutations including 1 missense mutation (L106F). The PLTP activity was unchanged in the p.L106F mutation. The frequency of the rs2294213 minor allele was markedly increased in the HyperA group (7.0%) in comparison with a control group (4.3%) and the hypoalphalipoproteinemia group (2.2%). Moreover, rs2294213 was strongly associated with HDL-C levels. Linear regression models predict that possession of the rs2294213 minor allele increases HDL-C independent of triglycerides. These findings extend the association of rs2294213 with HDL-C levels into the extremes of the HDL distribution.

Abstract

Note 48 Concepts and tools in genetics and genomics 48 Introduction 48 Genes and chromosomes 49 Gene expression and protein synthesis - regulation of gene expression 49 DNA and human diversity 51 Complex, multifactorial disorders 53 Approaches used to conduct genetic studies 53 Expression analyses: RNA-based studies 57 Proteome analyses: protein-based studies 59 The new frontier: systems biology 60 Research-related issues unique to the study of pain alleles 60 Genetics and pain sensitivity 60 The complexities of determining genetic risk factors for chronic pain 60 Pharmacogenetics and analgesic drugs 61 Molecular biologic tools in the elucidation of pain mechanisms and drug discovery 63 References 63 The genetics of pain is a complex trait, due to a combination of genetic and environmental factors.

Abstract

Purpose: In a sample of family caregivers (FCs) of patients with prostate cancer who were to begin radiation therapy (RT), the purposes were to determine the prevalence and severity of depression, anxiety, pain, sleep disturbance, and fatigue; determine the relationships among these symptoms and between these symptoms and functional status and quality of life (QOL); evaluate for differences in functional status and QOL between FCs with low and high levels of these symptoms; and determine which factors predicted FCs' functional status and QOL. Patients and Methods: FCs were recruited before patients initiated RT and completed self-report questionnaires that evaluated demographic characteristics, symptoms, functional status, and QOL. Results: Sixty female FCs participated in the study. On the basis of established cut point scores for each symptom questionnaire, 12.2% of the FCs had clinically meaningful levels of depression, 40.7% anxiety, 15.0% pain, 36.7% sleep disturbance, 33.3% morning fatigue, and 30.0% evening fatigue. FCs who were older and who had lower levels of state anxiety and higher levels of depression, morning fatigue, and pain reported significantly poorer functional status (R2 = 38.7%). FCs who were younger, had more years of education, were working, and who had higher levels of depression, morning fatigue, sleep disturbance, and lower levels of evening fatigue reported significantly lower QOL scores (R2 = 70.1%). Conclusion: A high percentage of FCs experienced clinically meaningful levels of a variety of symptoms. These symptoms have a negative impact on the FCs' functional status and QOL.

Abstract

Aims: Recent large association studies have revealed associations between genetic polymorphisms and myocardial infarction and coronary heart disease (CHD). We performed a replication study of 10 polymorphisms and CHD in a population with familial hypercholesterolemia (FH), individuals at extreme risk of CHD. Methods and results: We genotyped 10 polymorphisms in 2145 FH patients and studied the association between these polymorphisms and CHD in Cox proportional hazards models. We confirmed the associations between four polymorphisms and CHD, the rs1151640 polymorphism in the olfactory receptor family 13 subfamily G member 1 (OR13G1) gene (HR 1.14, 95% CI 1.01-1.28, P = 0.03), the rs11881940 polymorphism in the heterogeneous nuclear ribonucleoprotein U-like 1 (HNRPUL1) gene (HR 1.27, 95% CI 1.07-1.51, P = 0.007), the rs3746731 polymorphism in the complement component 1 q subcomponent receptor 1 (CD93) gene (HR 1.26, 95% CI 1.06-1.49, P = 0.01), and the rs10757274 polymorphism near the cyclin-dependent kinase N2A and N2B (CDKN2A and CDKN2B) genes (HR 1.39, 95% CI 1.15-1.69, P < 0.001). Conclusion: We confirmed previously found associations between four polymorphisms and CHD, but refuted associations for six other polymorphisms in our large FH population. These findings stress the importance of replication before genetic information can be implemented in the prediction of CHD.

Abstract

Purpose/Objectives: To apply the Hanahan and Weinberg conceptual framework for tumor development to the specific biomarkers observed or expressed in ovarian cancer. Data Sources: Data-based publications, topical reviews, and book chapters. Data Synthesis: Articles specific to ovarian cancer were reviewed to examine whether the six rules from the Hanahan and Weinberg conceptual framework were applicable to biomarkers of ovarian cancer. This approach allows for the application of a general framework for the development of solid tumors to the development of ovarian cancer. Conclusions: The six rules for tumor cell development outlined in the Hanahan and Weinberg conceptual framework are applicable to biomarkers expressed or observed in patients with ovarian cancer. Implications for Nursing: Oncology nurses can enhance their clinical teaching by integrating this information into their practice. Nurses who conduct research on ovarian cancer can use this framework to guide the selection of biomarker(s) for these studies. Finally, nurse educators can use this framework when teaching students key concepts in the care of patients with cancer.

Abstract

The aims of this replication study were to determine if subgroups of oncology outpatients receiving active treatment could be identified based on their experience with the symptoms of fatigue, sleep disturbance, depression, and pain; whether patients in these subgroups differed on selected demographic, disease, and treatment characteristics; and if patients in these subgroups differed on functional status and quality of life (QOL). A convenience sample of 228 oncology outpatients was recruited from seven outpatient settings in Israel. Patients completed a demographic questionnaire, a Karnofsky Performance Status score, the Multidimensional Quality of Life Scale-Cancer, the Lee Fatigue Scale, the General Sleep Disturbance Scale, the Center for Epidemiological Studies-Depression Scale, and a numeric rating scale of worst pain intensity. Cluster analysis was used to identify the patient subgroups based on their symptom experience. Four relatively distinct patient subgroups were identified based on their experiences with the above symptoms (i.e., low levels of all four symptoms (32.9%), low levels of pain and high levels of fatigue (18.0%), high levels of pain and moderate levels of fatigue (42.5%), and high levels of all four symptoms (6.6%). No differences were found among the four subgroups on any demographic, disease, or treatment characteristics. The subgroup of patients who reported high levels of all four symptoms reported the worst functional status and poorest QOL. In conclusion, differences in the symptom experience of oncology outpatients suggest that patients may harbor different phenotypic characteristics (e.g., environmental or physiologic) or genetic determinants for experiencing symptoms that are independent of demographic, disease, and treatment characteristics.

Abstract

Fatigue is the most common and distressing symptom reported by patients undergoing radiation therapy (RT). However, limited information is available on the trajectories of fatigue, as well as on the predictors of interindividual variability in fatigue. This study evaluated a sample of patients who underwent RT for prostate cancer to examine how ratings of evening and morning fatigue changed from the time of simulation to four months after the completion of RT and to investigate whether specific patient, disease, and symptom characteristics predicted the initial levels of fatigue and/or characteristics of the trajectories of evening and morning fatigue. Using hierarchical linear modeling, a large amount of interindividual variability was demonstrated in the trajectories of evening and morning fatigue. Findings from this study suggest that younger men with a higher level of fatigue at the time of the simulation visit were at increased risk for higher levels of evening and morning fatigue over the course of RT. In addition, the level of morning fatigue over the course of RT appears to depend on the patient's level of depression at the time of the simulation visit. In future studies, the use of hierarchical linear modeling as an analytic tool will assist in the identification of patients who are most at risk for prolonged fatigue trajectories. This type of analysis may lead to the identification of subgroups of patients who are at higher risk for negative outcomes and who require different types of interventions for the fatigue associated with RT.

Abstract

Low serum HDL-cholesterol (HDL-C) is a major risk factor for coronary artery disease. We performed targeted genotyping of a 12.4 Mb linked region on 16q to test for association with low HDL-C by using a regional-tag SNP strategy. We identified one SNP, rs2548861, in the WW-domain-containing oxidoreductase (WWOX) gene with region-wide significance for low HDL-C in dyslipidemic families of Mexican and European descent and in low-HDL-C cases and controls of European descent (p = 6.9 × 10-7). We extended our investigation to the population level by using two independent unascertained population-based Finnish cohorts, the cross-sectional METSIM cohort of 4,463 males and the prospective Young Finns cohort of 2,265 subjects. The combined analysis provided p = 4 × 10-4 to 2 × 10-5. Importantly, in the prospective cohort, we observed a significant longitudinal association of rs2548861 with HDL-C levels obtained at four different time points over 21 years (p = 0.003), and the T risk allele explained 1.5% of the variance in HDL-C levels. The rs2548861 resides in a highly conserved region in intron 8 of WWOX. Results from our in vitro reporter assay and electrophoretic mobility-shift assay demonstrate that this region functions as a cis-regulatory element whose associated rs2548861 SNP has a specific allelic effect and that the region forms an allele-specific DNA-nuclear-factor complex. In conclusion, analyses of 9,798 subjects show significant association between HDL-C and a WWOX variant with an allele-specific cis-regulatory function.

Abstract

The majority of the research on the various aspects of symptom management has focused on individual symptoms. However, patients with cancer often experience multiple symptoms simultaneously as a result of their disease and treatment. In 2001, symptom management researchers began to study the impact of symptom clusters on patient outcomes. Over the past 6 years, a number of conceptual reviews as well as several research studies have been published on symptom clusters in oncology patients. This paper summarizes the conceptual basis for symptom cluster research, describes two conceptual approaches to symptom cluster research, and discusses the implications of symptom clusters for quality-of-life research. The paper concludes with an enumeration of the critical considerations that need to be addressed if this area of scientific inquiry is to move forward.