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Pandiri A.R.,National Health Research Institute | Pandiri A.R.,Experimental Pathology Laboratories Inc. | Sills R.C.,National Health Research Institute | Hoenerhoff M.J.,National Health Research Institute | And 9 more authors.
Toxicologic Pathology

Aloe vera is one of the most commonly used botanicals for various prophylactic and therapeutic purposes. Recently, NTP/NCTR has demonstrated a dose-dependent increase in large intestinal tumors in F344 rats chronically exposed to Aloe barbadensis Miller (Aloe vera) non-decolorized whole leaf extract (AVNWLE) in drinking water. The morphological and molecular pathways of AVNWLE-induced large intestinal tumors in the F344 rats were compared to human colorectal cancer (hCRC) literature. Defined histological criteria were used to compare AVNWLE-induced large intestinal tumors with hCRC. The commonly mutated genes (Kras, Ctnnb1, and Tp53) and altered signaling pathways (MAPK, WNT, and TGF-β) important in hCRC were evaluated within AVNWLE-induced large intestinal tumors. Histological evaluation of the large intestinal tumors indicated eight of twelve adenomas (Ads) and four of twelve carcinomas (Cas). Mutation analysis of eight Ads and four Cas identified point mutations in exons 1 and 2 of the Kras gene (two of eight Ads, two of four Cas), and in exon 2 of the Ctnnb1 gene (three of eight Ads, one of four Cas). No Tp53 (exons 5-8) mutations were found in Ads or Cas. Molecular pathways important in hCRC such as MAPK, WNT, and TGF-β signaling were also altered in AVNWLE-induced Ads and Cas. In conclusion, the AVNWLE-induced large intestinal tumors in F344 rats share several similarities with hCRC at the morphological and molecular levels. © Society of Toxicologic Pathology 2011. Source

Moore A.B.,National Health Research Institute | Yu L.,National Health Research Institute | Swartz C.D.,Integrated Laboratory Systems Incorporated | Zheng X.,National Health Research Institute | And 6 more authors.
Cell Communication and Signaling

Background: Uterine leiomyomas (fibroids) are benign smooth muscle tumors that often contain an excessive extracellular matrix (ECM). In the present study, we investigated the interactions between human uterine leiomyoma (UtLM) cells and uterine leiomyoma-derived fibroblasts (FB), and their importance in cell growth and ECM protein production using a coculture system. Results: We found enhanced cell proliferation, and elevated levels of ECM collagen type I and insulin-like growth factor-binding protein-3 after coculturing. There was also increased secretion of vascular endothelial growth factor, epidermal growth factor, fibroblast growth factor-2, and platelet derived growth factor A and B in the media of UtLM cells cocultured with FB. Protein arrays revealed increased phosphorylated receptor tyrosine kinases (RTKs) of the above growth factor ligands, and immunoblots showed elevated levels of the RTK downstream effector, phospho-mitogen activated protein kinase 44/42 in cocultured UtLM cells. There was also increased secretion of transforming growth factor-beta 1 and 3, and immunoprecipitated transforming growth factor-beta receptor I from cocultured UtLM cells showed elevated phosphoserine expression. The downstream effectors phospho-small mothers against decapentaplegic -2 and -3 protein (SMAD) levels were also increased in cocultured UtLM cells. However, none of the above effects were seen in normal myometrial cells cocultured with FB. The soluble factors released by tumor-derived fibroblasts and/or UtLM cells, and activation of the growth factor receptors and their pathways stimulated the proliferation of UtLM cells and enhanced the production of ECM proteins. Conclusions: These data support the importance of interactions between fibroid tumor cells and ECM fibroblasts in vivo, and the role of growth factors, and ECM proteins in the pathogenesis of uterine fibroids. © 2010 Moore et al; licensee BioMed Central Ltd. Source

Wong J.R.,Radiation Epidemiology Branch | Tucker M.A.,Human Genetics Program | Kleinerman R.A.,Radiation Epidemiology Branch | Devesa S.S.,Biostatistics Branch
JAMA Ophthalmology

IMPORTANCE Several studies have found no temporal or demographic differences in the incidence of retinoblastoma except for age at diagnosis, whereas other studies have reported variations in incidence by sex and race/ethnicity. OBJECTIVE To examine updated US retinoblastoma incidence patterns by sex, age at diagnosis, laterality, race/ethnicity, and year of diagnosis. DESIGN, SETTING, AND PARTICIPANTS The Surveillance, Epidemiology, and End Results (SEER) databases were examined for retinoblastoma incidence patterns by demographic and tumor characteristics.We studied 721 children in SEER 18 registries, 659 in SEER 13 registries, and 675 in SEER 9 registries. MAIN OUTCOMES AND MEASURES Incidence rates, incidence rate ratios (IRRs), and annual percent changes in rates. RESULTS During 2000-2009 in SEER 18, there was a significant excess of total retinoblastoma among boys compared with girls (IRR, 1.18; 95%CI, 1.02 to 1.36), in contrast to earlier reports of a female predominance. Bilateral retinoblastoma among white Hispanic boys was significantly elevated relative to white non-Hispanic boys (IRR, 1.81; 95%CI, 1.22 to 2.79) and white Hispanic girls (IRR, 1.75; 95%CI, 1.11 to 2.91) because of less rapid decreases in bilateral rates since the 1990s among white Hispanic boys than among the other groups. Retinoblastoma rates among white non-Hispanics decreased significantly since 1992 among those younger than 1 year and since 1998 among those with bilateral disease. CONCLUSIONS AND RELEVANCE Although changes in the availability of prenatal screening practices for retinoblastoma may have contributed to these incidence patterns, further research is necessary to determine their actual effect on the changing incidence of retinoblastoma in the US population. In addition, consistent with other cancers, an excess of retinoblastoma diagnosed in boys suggests a potential effect of sex on cancer origin. © 2014 American Medical Association. All rights reserved. Source

Mondul A.M.,Nutritional Epidemiology Branch | Yu K.,Biostatistics Branch | Wheeler W.,Management Information Services Inc. | Zhang H.,Fudan University | And 18 more authors.
Human Molecular Genetics

Retinol is one of the most biologically active forms of vitamin A and is hypothesized to influence a wide range of human diseases including asthma, cardiovascular disease, infectious diseases and cancer. We conducted a genome-wide association study of 5006 Caucasian individuals drawn from two cohorts of men: the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study and the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. We identified two independent single-nucleotide polymorphisms associated with circulating retinol levels, which are located near the transthyretin (TTR) and retinol binding protein 4 (RBP4) genes which encode major carrier proteins of retinol: rs1667255 (P =2.30× 10 -17) and rs10882272 (P =6.04× 10 -12). We replicated the association with rs10882272 in RBP4 in independent samples from the Nurses' Health Study and the Invecchiare in Chianti Study (InCHIANTI) that included 3792 women and 504 men (P =9.49× 10 -5), but found no association for retinol with rs1667255 in TTR among women, thus suggesting evidence for gender dimorphism (P-interaction=1.31× 10 -5). Discovery of common genetic variants associated with serum retinol levels may provide further insight into the contribution of retinol and other vitamin A compounds to the development of cancer and other complex diseases. © The Author 2011. Published by Oxford University Press. All rights reserved. Source

Guertin K.A.,Nutritional Epidemiology Branch | Moore S.C.,Nutritional Epidemiology Branch | Sampson J.N.,Biostatistics Branch | Huang W.-Y.,Occupational and Environmental Epidemiology Branch | And 4 more authors.
American Journal of Clinical Nutrition

Background: Metabolomics is an emerging field with the potential to advance nutritional epidemiology; however, it has not yet been applied to large cohort studies. Objectives: Our first aim was to identify metabolites that are biomarkers of usual dietary intake. Second, among serum metabolites correlated with diet, we evaluated metabolite reproducibility and required sample sizes to determine the potential for metabolomics in epidemiologic studies. Design: Baseline serum from 502 participants in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial was analyzed by using ultra-high- performance liquid-phase chromatography with tandem mass spectrometry and gas chromatography-mass spectrometry. Usual intakes of 36 dietary groups were estimated by using a food-frequency questionnaire. Dietary biomarkers were identified by using partial Pearson's correlations with Bonferroni correction for multiple comparisons. Intraclass correlation coefficients (ICCs) between samples collected 1 y apart in a subset of 30 individuals were calculated to evaluate intraindividual metabolite variability. Results: We detected 412 known metabolites. Citrus, green vegetables, red meat, shellfish, fish, peanuts, rice, butter, coffee, beer, liquor, total alcohol, and multivitamins were each correlated with at least one metabolite (P < 1.093. 10-6; r = -0.312 to 0.398); in total, 39 dietary biomarkers were identified. Some correlations (citrus intake with stachydrine) replicated previous studies; others, such as peanuts and tryptophan betaine, were novel findings. Other strong associations included coffee (with trigonelline-N-methylnicotinate and quinate) and alcohol (with ethyl glucuronide). Intraindividual variability in metabolite levels (1-y ICCs) ranged from 0.27 to 0.89. Large, but attainable, sample sizes are required to detect associations between metabolites and disease in epidemiologic studies, further emphasizing the usefulness of metabolomics in nutritional epidemiology. Conclusions: We identified dietary biomarkers by using metabolomics in an epidemiologic data set. Given the strength of the associations observed, we expect that some of these metabolites will be validated in future studies and later used as biomarkers in large cohorts to study diet-disease associations. The PLCO trial was registered at clinicaltrials.gov as NCT00002540. © 2014 American Society for Nutrition. Source

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