GenUs BioSystems Inc.

Northbrook, IL, United States

GenUs BioSystems Inc.

Northbrook, IL, United States
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Mao J.,University of Missouri | Zhang X.,University of Missouri | Sieli P.T.,University of Missouri | Falduto M.T.,GenUs BioSystems Inc. | And 2 more authors.
Proceedings of the National Academy of Sciences of the United States of America | Year: 2010

Diet during pregnancy influences the future health of a woman's offspring, with outcomes differing depending on the child's sex. Because the placenta buffers the fetus from the mother, we examined the impact of diet and fetal sex on placental gene expression in mice fed either a very-high-fat, low-fat, chow diet of intermediate caloric density. At day 12.5 of pregnancy, placental RNA was extracted and analyzed by microarray. The expression of 1,972 genes was changed more than 2-fold (P < 0.05) in comparisons across diet in at least one of the three groups. Female placentae demonstrated more striking alterations in gene expression in response to maternal diet than male placentae. Notably, each diet provided a distinctive signature of sexually dimorphic genes, with expression generally higher in genes (651 out of 700) from female placentae than those from male placentae. Several genes normally considered as characteristic of kidney function were affected by diet, including genes regulating ion balance and chemoreception. The placenta also expressed most of the known olfactory receptor genes (Olfr), which may allow the placenta to sense odorant molecules and other minor dietary components, with transcript levels of many of these genes influenced by diet and fetal sex. In conclusion, gene expression in the murine placenta is adaptive and shaped by maternal diet. It also exhibits pronounced sexual dimorphism, with placentae of females more sensitive to nutritional perturbations than placentae of males.

John-Aryankalayil M.,U.S. National Cancer Institute | Palayoor S.T.,U.S. National Cancer Institute | Cerna D.,U.S. National Cancer Institute | Simone II C.B.,U.S. National Cancer Institute | And 3 more authors.
Radiation Research | Year: 2010

To examine the possibility of using fractionated radiation in a unique way with molecular targeted therapy, gene expression profiles of prostate carcinoma cells treated with 10 Gy radiation administered either as a single dose or as fractions of 2 Gy × 5 and 1 Gy × 10 were examined by microarray analysis. Compared to the single dose, the fractionated irradiation resulted in significant increases in differentially expressed genes in both cell lines, with more robust changes in PC3 cells than in DU145 cells. The differentially expressed genes (> two fold change; P < 0.05) were clustered and their ontological annotations evaluated. In PC3 cells genes regulating immune and stress response, cell cycle and apoptosis were significantly up-regulated by multifractionated radiation compared to single-dose radiation. Ingenuity Pathway Analysis (IPA) of the differentially expressed genes revealed that immune response and cardiovascular genes were in the top functional category in PC3 cells and cell-to-cell signaling in DU145 cells. RT-PCR analysis showed that a flexure point for gene expression occurred at the 6th8th fraction and AKT inhibitor perifosine produced enhanced cell killing after 1 Gy × 8 fractionated radiation in PC3 and DU145 cells compared to single dose. This study suggests that fractionated radiation may be a uniquely exploitable, non-oncogene-addiction stress pathway for molecular therapeutic targeting. © 2010 by Radiation Research Society.

Roberts R.M.,University of Missouri | Katayama M.,University of Missouri | Magnuson S.R.,GenUs BioSystems Inc. | Falduto M.T.,GenUs BioSystems Inc. | Torres K.E.O.,GenUs BioSystems Inc.
Biology of Reproduction | Year: 2011

In invertebrates and amphibians, informational macromolecules in egg cytoplasm are organized to provide direction to the formation of embryonic lineages, but it is unclear whether vestiges of such prepatterning exist in mammals. Here we examined whether twin blastomeres from 2-cell stage mouse embryos differ in mRNA content. mRNA from 26 blastomeres derived from 13 embryos approximately mid-way through their second cell cycle was subjected to amplification. Twenty amplified samples were hybridized to arrays. Of those samples that hybridized successfully, 12 samples in six pairs were used in the final analysis. Probes displaying normalized values >0.25 (n = 4573) were examined for consistent bias in expression within blastomere pairs. Although transcript content varied between both individual embryos and twin blastomeres, no consistent asymmetries were observed for the majority of genes, with only 178 genes displaying a >1.4-fold difference in expression across all six pairs. Although class discovery clustering showed that blastomere pairs separated into two distinct groups in terms of their differentially expressed genes, when the data were tested for significance of asymmetrical expression, only 39 genes with >1.4-fold change ratios in six of six blastomere pairs passed the two-sample t-test (P < 0.05). Transcripts encoding proteins implicated in RNA processing and cytoskeletal organization were among the most abundant, differentially distributed mRNA, suggesting that a stochastically based lack of synchrony in cell cycle progression between the two cells might explain at least some and possibly all of the asymmetries in transcript composition. © 2011 by the Society for the Study of Reproduction, Inc.

Simone II C.B.,University of Pennsylvania | Simone II C.B.,U.S. National Institutes of Health | John-Aryankalayil M.,U.S. National Institutes of Health | Palayoor S.T.,U.S. National Institutes of Health | And 5 more authors.
Translational Oncology | Year: 2013

We assessed changes in cell lines of varying p53 status after various fractionation regimens to determine if p53 influences gene expression and if multifractionated (MF) irradiation can induce molecular pathway changes. LNCaP (p53 wild-type), PC3 (p53 null), and DU145 (p53 mutant) prostate carcinoma cells received 5 and 10 Gy as single-dose (SD) or MF (0.5 Gy × 10, 1 Gy × 10, and 2 Gy × 5) irradiation to simulate hypofractionated and conventionally fractionated prostate radiotherapies, respectively. mRNA analysis revealed 978 LNCaP genes differentially expressed (greater than two-fold change, P <.05) after irradiation. Most were altered with SD (69%) and downregulated (75%). Fewer PC3 (343) and DU145 (116) genes were induced, with most upregulated (87%, 89%) and altered with MF irradiation. Gene ontology revealed immune response and interferon genes most prominently expressed after irradiation in PC3 and DU145. Cell cycle regulatory (P = 9.23 × 10-73, 14.2% of altered genes, nearly universally downregulated) and DNA replication/repair (P = 6.86 × 10-30) genes were most prominent in LNCaP. Stress response and proliferation genes were altered in all cell lines. p53-activated genes were only induced in LNCaP. Differences in gene expression exist between cell lines and after varying irradiation regimens that are p53 dependent. As the duration of changes is ≥24 hours, it may be possible to use radiation-inducible targeted therapy to enhance the efficacy of molecular targeted agents. © 2013 Neoplasia Press, Inc. All rights reserved.

John-Aryankalayil M.,U.S. National Cancer Institute | Palayoor S.T.,U.S. National Cancer Institute | Makinde A.Y.,U.S. National Cancer Institute | Cerna D.,U.S. National Cancer Institute | And 4 more authors.
Radiation Research | Year: 2012

We have previously demonstrated that prostate carcinoma cells exposed to fractionated radiation differentially expressed more genes compared to single-dose radiation. To understand the role of miRNA in regulation of radiation-induced gene expression, we analyzed miRNA expression in LNCaP, PC3 and DU145 prostate cancer cells treated with single-dose radiation and fractionated radiation by microarray. Selected miRNAs were studied in RWPE-1 normal prostate epithelial cells by RT-PCR. Fractionated radiation significantly altered more miRNAs as compared to single-dose radiation. Downregulation of oncomiR-17-92 cluster was observed only in the p53 positive LNCaP and RWPE-1 cells treated with single-dose radiation and fractionated radiation. Comparison of miRNA and mRNA data by IPA target filter analysis revealed an inverse correlation between miR-17-92 cluster and several targets including TP53INP1 in p53 signaling pathway. The base level expressions of these miRNAs were significantly different among the cell lines and did not predict the radiation outcome. Tumor suppressor miR-34a and let-7 miRNAs were upregulated by fractionated radiation in radiosensitive LNCaP (p53 positive) and PC3 (p53-null) cells indicating that radiation-induced miRNA expression may not be regulated by p53 alone. Our data support the potential for using fractionated radiation to induce molecular targets and radiation-induced miRNAs may have a significant role in predicting radiosensitivity. © 2012 by Radiation Research Society.

Palayoor S.T.,U.S. National Cancer Institute | John-Aryankalayil M.,U.S. National Cancer Institute | Makinde A.Y.,U.S. National Cancer Institute | Falduto M.T.,GenUs Biosystems Inc. | And 2 more authors.
Molecular Cancer Research | Year: 2014

Although modern radiotherapy technologies can precisely deliver higher doses of radiation to tumors, thus, reducing overall radiation exposure to normal tissues, moderate dose, and normal tissue toxicity still remains a significant limitation. The present study profiled the global effects on transcript and miR expression in human coronary artery endothelial cells using single-dose irradiation (SD, 10 Gy) or multifractionated irradiation (MF, 2Gy x 5) regimens. Longitudinal time points were collected after an SD or final dose of MF irradiation for analysis using Agilent Human Gene Expression and miRNA microarray platforms. Compared with SD, the exposure to MF resulted in robust transcript and miR expression changes in terms of the number and magnitude. For data analysis, statistically significant mRNAs (2-fold) and miRs (1.5-fold) were processed by Ingenuity Pathway Analysis to uncover miRs associated with target transcripts from several cellular pathways after irradiation. Interestingly, MF radiation induced a cohort of mRNAs and miRs that coordinate the induction of immune response pathway under tight regulation. In addition, mRNAs and miRs associated with DNA replication, recombination and repair, apoptosis, cardiovascular events, and angiogenesis were revealed. Implications: Radiation-induced alterations in stress and immune response genes in endothelial cells contribute to changes in normal tissue and tumor microenvironment, and affect the outcome of radiotherapy. ©2014 AACR.

Palayoor S.T.,U.S. National Cancer Institute | J-Aryankalayil M.,U.S. National Cancer Institute | Makinde A.Y.,U.S. National Cancer Institute | Cerna D.,U.S. National Cancer Institute | And 3 more authors.
Journal of Cardiovascular Pharmacology | Year: 2012

Nonsteroidal anti-inflammatory drugs (NSAIDs) have come under scrutiny because of the gastrointestinal, renal, and cardiovascular toxicity associated with prolonged use of these drugs. The purpose of this study was to identify molecular targets for NSAIDs related to cellular toxicity with a view to optimize drug efficacy in the clinic. Coronary artery smooth muscle cells and endothelial cells were treated with low (clinically achievable) and high (typically used in preclinical studies) concentrations of celecoxib, NS398, and ibuprofen for 24 hours. NSAIDs-induced gene expression changes were evaluated by microarray analysis and validated by real-time reverse-transcription polymerase chain reaction and western blotting. The functional significance of differentially expressed genes was evaluated by Ingenuity Pathway Analysis. At high concentrations, NSAIDs altered the expression of genes regulating cell proliferation and cell death. NSAIDs also altered genes associated with cardiovascular functions including inflammation, thrombosis, fibrinolysis, coronary artery disease, and hypertension. The gene expression was most impacted by ibuprofen, celecoxib, and NS398, in that order. This study revealed that NSAIDs altered expression of an array of genes associated with cardiovascular events and emphasizes the potential for fingerprinting drugs in preclinical studies to assess the potential drug toxicity and to optimize the drug efficacy in clinical settings. Copyright © 2012 by Lippincott Williams & Wilkins.

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