Citations

Abstract The presence of regulatory T cells (Treg) in solid tumors is known to play a role in patient survival in ovarian cancer and other malignancies. We assessed inherited genetic variations via 749 tag single-nucleotide polymorphisms (SNP) in 25 Treg-associated genes (CD28, CTLA4, FOXP3, IDO1, IL10, IL10RA, IL15, 1L17RA, IL23A, IL23R, IL2RA, IL6, IL6R, IL8, LGALS1, LGALS9, MAP3K8, STAT5A, STAT5B, TGFB1, TGFB2, TGFB3, TGFBR1, TGRBR2, and TGFBR3) in relation to ovarian cancer survival. We analyzed genotype and overall survival in 10,084 women with invasive epithelial ovarian cancer, including 5,248 high-grade serous, 1,452 endometrioid, 795 clear cell, and 661 mucinous carcinoma cases of European descent across 28 studies from the Ovarian Cancer Association Consortium (OCAC). The strongest associations were found for endometrioid carcinoma and IL2RA SNPs rs11256497 [HR, 1.42; 95% confidence interval (CI), 1.22–1.64; P = 5.7 × 10−6], rs791587 (HR, 1.36; 95% CI, 1.17–1.57; P = 6.2 × 10−5), rs2476491 (HR, = 1.40; 95% CI, 1.19–1.64; P = 5.6 × 10−5), and rs10795763 (HR, 1.35; 95% CI, 1.17–1.57; P = 7.9 × 10−5), and for clear cell carcinoma and CTLA4 SNP rs231775 (HR, 0.67; 95% CI, 0.54–0.82; P = 9.3 × 10−5) after adjustment for age, study site, population stratification, stage, grade, and oral contraceptive use. The rs231775 allele associated with improved survival in our study also results in an amino acid change in CTLA4 and previously has been reported to be associated with autoimmune conditions. Thus, we found evidence that SNPs in genes related to Tregs seem to play a role in ovarian cancer survival, particularly in patients with clear cell and endometrioid epithelial ovarian cancer. Cancer Immunol Res; 2(4); 332–40. ©2014 AACR.

Abstract Purpose: Ovarian cancer has a high recurrence and mortality rate. A barrier to improved outcomes includes a lack of accurate models for preclinical testing of novel therapeutics. Experimental Design: Clinically relevant, patient-derived tumorgraft models were generated from sequential patients and the first 168 engrafted models are described. Fresh ovarian, primary peritoneal, and fallopian tube carcinomas were collected at the time of debulking surgery and injected intraperitoneally into severe combined immunodeficient mice. Results: Tumorgrafts demonstrated a 74% engraftment rate with microscopic fidelity of primary tumor characteristics. Low-passage tumorgrafts also showed comparable genomic aberrations with the corresponding primary tumor and exhibit gene set enrichment of multiple ovarian cancer molecular subtypes, similar to patient tumors. Importantly, each of these tumorgraft models is annotated with clinical data and for those that have been tested, response to platinum chemotherapy correlates with the source patient. Conclusions: Presented herein is the largest known living tumor bank of patient-derived, ovarian tumorgraft models that can be applied to the development of personalized cancer treatment. Clin Cancer Res; 20(5); 1288–97. ©2014 AACR.

AbstractResearch demonstrates that patients with fibromyalgia who have higher positive and lower negative affect have lower symptom burden. Affect has been shown to be associated with resilience. This study examined the relationship between affect, resilience and fibromyalgia symptom burden in a clinical sample of patients with fibromyalgia. We hypothesized that (a) positive and negative affect would be associated with fibromyalgia symptom burden; (b) resilience would be associated with positive and negative affect; (c) resilience would be associated with fibromyalgia symptom burden; and (d) the connection between resilience and fibromyalgia symptom burden would be mediated by both positive and negative affect. A sample of 858 patients with fibromyalgia completed questionnaires. Mediation modelling revealed statistically significant direct effects of resilience on fibromyalgia symptom burden (β = −0.10, P < 0.001) and statistically significant indirect effects of resilience on fibromyalgia symptom burden through affect (β = −0.36, P < 0.001), suggesting that both resilience and affect influence fibromyalgia symptom burden. Our results suggest that improving affect through resiliency training could be studied as a modality for improving fibromyalgia symptom burden. Copyright © 2013 John Wiley & Sons, Ltd.

Key Points The tumor microenvironment drives myeloma cell clonogenic growth and self-renewal through GDF15.

Background— Reduced low forced expiratory volume in 1 second (FEV 1 ) is reportedly associated with an increased risk of atrial fibrillation (AF). Extant reports do not provide separate estimates for never smokers or for blacks, who incongruously have lower AF incidence than whites. Methods and Results— We examined 15 004 middle-aged blacks and whites enrolled in the Atherosclerosis Risk in Communities (ARIC) cohort study. Standardized spirometry data were collected at the baseline examination. Incident AF was identified from the first among the following: International Classification of Diseases codes for AF on hospital discharge records or death certificates or 12-lead ECGs performed during 3 triennial follow-up visits. Over an average follow-up of 17.5 years, a total of 1691 participants (11%) developed new-onset AF. The rate of incident AF was inversely associated with FEV 1 in each of the 4 race and sex groups. After multivariable adjustment for traditional cardiovascular disease risk factors and height, hazard ratios of AF comparing the lowest with the highest quartile of FEV 1 were 1.37 (95% confidence interval, 1.02–1.83) for white women, 1.49 (95% confidence interval, 1.16–1.91) for white men, 1.63 (95% confidence interval, 1.00–2.66) for black women, and 2.36 (95% confidence interval, 1.30–4.29) for black men. The above associations were observed across all smoking status categories. Moderate/severe airflow obstruction (FEV 1 /forced vital capacity <0.70 and FEV 1 < 80% of predicted value) was also associated with higher AF incidence. Conclusions— In this large population-based study with a long-term follow-up, reduced FEV 1 and obstructive respiratory disease were associated with a higher AF incidence after adjustment for measured confounders.

Chronic kidney disease (CKD) is an increasing concern in the United States due to its rapidly rising prevalence, particularly among African Americans. Epigenetic DNA methylation markers are becoming important biomarkers of chronic diseases such as CKD. To better understand how these methylation markers play a role in kidney function, we measured 26,428 DNA methylation sites in 972 African Americans from the Genetic Epidemiology Network of Arteriopathy (GENOA) study. We then evaluated (1) whether epigenetic markers are associated with estimated glomerular filtration rate (eGFR), (2) whether the significantly associated markers are also associated with traditional risk factors and/or novel biomarkers for eGFR, and (3) how much additional variation in eGFR is explained by epigenetic markers beyond established risk factors and biomarkers. The majority of methylation markers most significantly associated with eGFR (24 out of the top 30) appeared to function, at least in part, through pathways related to aging, inflammation, or cholesterol. However, six epigenetic markers were still able to significantly predict eGFR after adjustment for other risk factors. This work shows that epigenetic markers may offer valuable new insight into the complex pathophysiology of CKD in African Americans.

Objective: We investigated ADAMTS13 (a disintegrin-like and metalloprotease with thrombospondin type 1 motif, member 13) messenger RNA levels as a biomarker of disease features in systemic lupus erythematosus. Methods: We measured and compared messenger RNA (mRNA) levels of ADAMTS13 in peripheral blood cells in patients with systemic lupus erythematosus and healthy control subjects by whole-genome microarray. We retrospectively analyzed the correlations of ADAMTS13 mRNA expression with clinical features, laboratory parameters, therapeutic features, and disease activity (according to the Systemic Lupus Erythematosus Disease Activity Index). We also examined the association of three single nucleotide polymorphisms (rs4962145, rs2285467, and rs685523) of the ADAMTS13 gene with patient characteristics. Results: In 309 patients, the median ADAMTS13 mRNA expression levels were significantly higher in blood cells of systemic lupus erythematosus patients than in 23 healthy controls ( p = .03). Notably, ADAMTS13 mRNA expression levels were significantly higher in systemic lupus erythematosus patients with a history of stroke ( p = .02) or transient ischemic attack ( p = .02). Among the three single nucleotide polymorphisms analyzed, rs2285467 was significantly associated with stroke ( p = .03) and anticardiolipin antibodies ( p = .04). Conclusions: Increased expression of ADAMTS13 mRNA in blood cells is associated with the presence of ischemic cerebrovascular disease in systemic lupus erythematosus patients and suggests a potential role for ADAMTS13 in the pathogenesis of ischemic cerebrovascular disease in these patients.