Intake of Lycopene and other Carotenoids and Incidence of Uterine Leiomyomata: A Prospective Ultrasound Study

BACKGROUND: Uterine leiomyomata (UL) are the leading indication for hysterectomy in the United States. Dietary supplementation with lycopene was associated with reduced size and incidence of oviduct leiomyoma in the Japanese quail. Two US prospective cohort studies of women reported little association between intake of lycopene, or other carotenoids, and UL incidence. However, these studies relied on self-reported physician-diagnosed UL, which is prone to misclassification. OBJECTIVE: This study examines the association between dietary intake of carotenoids and UL incidence. DESIGN: Data were derived from the Study of the Environment, Lifestyle, and Fibroids, a prospective cohort study. Women completed self-administered baseline questionnaires on demographic characteristics, reproductive history, and lifestyle, including a 110-item validated food frequency questionnaire, from which dietary intakes of carotenoids-including alpha carotene, beta carotene, cryptoxanthin, lutein-zeaxanthin, and lycopene-and vitamin A were estimated. PARTICIPANTS/SETTING: One thousand two hundred thirty Black women aged 23 to 35 years who did not have a previous diagnosis of UL, cancer, or autoimmune disease were eligible for enrollment (2010-2012). Participants were residents of the Detroit, MI, metropolitan area. MAIN OUTCOME MEASURES: Transvaginal ultrasound was used to assess UL at baseline and 20, 40, and 60 months of follow-up. STATISTICAL ANALYSES PERFORMED: Cox regression was used to estimate hazard ratios and 95% CIs, adjusted for energy intake, age at menarche, education, body mass index, parity, age at first birth, years since last birth, current use of oral contraceptives or progestin-only injectables, alcohol intake, and cigarette smoking. RESULTS: Among 1,230 women without prevalent UL at baseline, 301 incident UL cases during follow-up were identified. Intakes of lycopene, other carotenoids, and vitamin A were not appreciably associated with UL incidence. Hazard ratios comparing quartiles 2 (2,376 to 3,397 μg/day), 3 (3,398 to 4,817 μg/day), and 4 (≥4,818 μg/day) with quartile 1 (\u3c2,376 μg/day) of lycopene intake were 1.03 (95% CI 0.72 to 1.47), 1.22 (95% CI 0.86 to 1.72), and 0.95 (95% CI 0.67 to 1.36), respectively. CONCLUSIONS: Study findings do not support the hypothesis that greater carotenoid intake is associated with reduced UL incidence

Clinical Development of Novel Drug-Radiotherapy Combinations.

Radiotherapy is a fundamental component of treatment for the majority of patients with cancer. In recent decades, technological advances have enabled patients to receive more targeted doses of radiation to the tumor, with sparing of adjacent normal tissues. There had been hope that the era of precision medicine would enhance the combination of radiotherapy with targeted anticancer drugs; however, this ambition remains to be realized. In view of this lack of progress, the FDA-AACR-ASTRO Clinical Development of Drug-Radiotherapy Combinations Workshop was held in February 2018 to bring together stakeholders and opinion leaders from academia, clinical radiation oncology, industry, patient advocacy groups, and the FDA to discuss challenges to introducing new drug-radiotherapy combinations to the clinic. This Perspectives in Regulatory Science and Policy article summarizes the themes and action points that were discussed. Intelligent trial design is required to increase the number of studies that efficiently meet their primary outcomes; endpoints to be considered include local control, organ preservation, and patient-reported outcomes. Novel approaches including immune-oncology or DNA-repair inhibitor agents combined with radiotherapy should be prioritized. In this article, we focus on how the regulatory challenges associated with defining a new drug-radiotherapy combination can be overcome to improve clinical outcomes for patients with cancer

Common variants near FRK/COL10A1 and VEGFA are associated with advanced age-related macular degeneration

Despite significant progress in the identification of genetic loci for age-related macular degeneration (AMD), not all of the heritability has been explained. To identify variants which contribute to the remaining genetic susceptibility, we performed the largest meta-analysis of genome-wide association studies to date for advanced AMD. We imputed 6 036 699 single-nucleotide polymorphisms with the 1000 Genomes Project reference genotypes on 2594 cases and 4134 controls with follow-up replication of top signals in 5640 cases and 52 174 controls. We identified two new common susceptibility alleles, rs1999930 on 6q21-q22.3 near FRK/COL10A1 [odds ratio (OR) 0.87; P = 1.1 × 10−8] and rs4711751 on 6p12 near VEGFA (OR 1.15; P = 8.7 × 10−9). In addition to the two novel loci, 10 previously reported loci in ARMS2/HTRA1 (rs10490924), CFH (rs1061170, and rs1410996), CFB (rs641153), C3 (rs2230199), C2 (rs9332739), CFI (rs10033900), LIPC (rs10468017), TIMP3 (rs9621532) and CETP (rs3764261) were confirmed with genome-wide significant signals in this large study. Loci in the recently reported genes ABCA1 and COL8A1 were also detected with suggestive evidence of association with advanced AMD. The novel variants identified in this study suggest that angiogenesis (VEGFA) and extracellular collagen matrix (FRK/COL10A1) pathways contribute to the development of advanced AMD

A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants.

This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/ng.3448Advanced age-related macular degeneration (AMD) is the leading cause of blindness in the elderly, with limited therapeutic options. Here we report on a study of >12 million variants, including 163,714 directly genotyped, mostly rare, protein-altering variants. Analyzing 16,144 patients and 17,832 controls, we identify 52 independently associated common and rare variants (P < 5 × 10(-8)) distributed across 34 loci. Although wet and dry AMD subtypes exhibit predominantly shared genetics, we identify the first genetic association signal specific to wet AMD, near MMP9 (difference P value = 4.1 × 10(-10)). Very rare coding variants (frequency <0.1%) in CFH, CFI and TIMP3 suggest causal roles for these genes, as does a splice variant in SLC16A8. Our results support the hypothesis that rare coding variants can pinpoint causal genes within known genetic loci and illustrate that applying the approach systematically to detect new loci requires extremely large sample sizes.We thank all participants of all the studies included for enabling this research by their participation in these studies. Computer resources for this project have been provided by the high-performance computing centers of the University of Michigan and the University of Regensburg. Group-specific acknowledgments can be found in the Supplementary Note. The Center for Inherited Diseases Research (CIDR) Program contract number is HHSN268201200008I. This and the main consortium work were predominantly funded by 1X01HG006934-01 to G.R.A. and R01 EY022310 to J.L.H

International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways.

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist