News Article | October 26, 2016
AURORA, Colo. (Oct. 11, 2016) - Researchers at the University of Colorado Anschutz Medical Campus along with colleagues at Johns Hopkins University and other institutions have conducted the largest ever genome sequencing of populations with African ancestry in the Americas. The scientists, for the first time, have created a massive genetic catalog of the African diaspora in this hemisphere. It offers a unique window into the striking genetic variety of the population while opening the door to new ways of understanding and treating diseases specific to this group. The study was published today in the journal Nature Communications. "The African Diaspora in the Western Hemisphere represents one of the largest forced migrations in history and had a profound impact on genetic diversity in modern populations," said the study's principal investigator Kathleen Barnes, PhD, director of the Colorado Center for Personalized Medicine at CU Anschutz. "Yet this group has been largely understudied." Barnes said those of African ancestry in the Americas suffer a disproportionate burden of disability, disease and death from common chronic illnesses like asthma, diabetes and other ailments. The reasons why, remain largely unknown. With that question in mind Barnes and her colleagues, with support from the NIH's National Heart, Lung and Blood Institute, created the `Consortium on Asthma among African-ancestry Populations in the Americas' or CAAPA. They sequenced the genome of 642 people of African ancestry from 15 North, Central and South American and Caribbean populations plus Yoruba-speaking individuals from Ibadan, Nigeria. The ultimate goal of the study is to better understand why they are more susceptible to asthma in the Americas. But the result was a wide-ranging genetic catalogue unlike any other. The African genome is the oldest and most varied on earth. Africa is where modern humans evolved before migrating to Europe, Asia and beyond. Barnes and her team are finding changes in the DNA of Africans in the Americas that put them at higher risk for certain diseases. Perhaps one reason for this is the amount of genetic material they carry from other populations including those of European ancestry and American Indians. "Patterns of genetic distance and sharing of single nucleotide variations among these populations reflect the unique population histories in each of the North, Central and South American and Caribbean island destinations of West African slaves, with their particular Western European colonial and Native American populations," the study said. For example, the researchers showed that the mean African ancestry varied widely among populations depending on where they were settled, from 27% of Puerto Ricans to 89% of Jamaicans. In places like the Dominican Republic, Brazil, Honduras and Colombia there was also significant Native American ancestry as well. Untangling this genetic history will take years, but Barnes said the catalogue is a good start. The data will serve as an important resource for disease mapping studies in those with African ancestry. "This will contribute to the public database and give clinicians more information to better predict and track human disease," Barnes said. "It will allow us to tailor clinical to specific individuals based on their ethnic and racial backgrounds." A companion paper demonstrating the clinical utility of the African diaspora genome catalog appears in the same issue of Nature Communications.
News Article | November 10, 2016
NEW ORLEANS, LA--(Marketwired - November 10, 2016) - Louisiana State University Health Sciences Center New Orleans (LSU Health New Orleans) and OmniSeq (OmniSeq®), a subsidiary of the Roswell Park Cancer Institute (RPCI), are now partnering to provide oncologists with comprehensive next generation sequencing of solid tumors for clinical decision support. "LSU Health New Orleans has an 85-year history as a premier healthcare institution in Louisiana with six professional schools and eight Centers of Excellence. We look forward to adding OmniSeq's cutting edge technology to the LSU Health New Orleans toolkit," said Carl Morrison, President and Chief Scientific Officer of OmniSeq. "Comprehensive genomic profiling should be the first step for all advanced stage solid tumors whenever targeted therapy is a treatment consideration," said Morrison. LSU Health New Orleans will utilize OmniSeq Comprehensive(SM), a pan-cancer tumor profiling diagnostic panel, to screen patients at their facilities. The 144-gene panel is New York State (NYS) CLEP-approved, the gold standard in clinical laboratory testing. Oncologists and patients at LSU Health New Orleans will receive personalized reports on the patients' individual genetic variants including: FDA-approved therapeutics, clinical trials for which the patient may qualify, and potential hereditary variants. OmniSeq Comprehensive utilizes the least amount of tissue of any commercially available comprehensive tumor profiling assay. To date, OmniSeq Comprehensive identified actionable variants -- including FDA-approved therapeutics and precision medicine trials -- for over 83% of patients tested. Through this partnership, LSUHSC will receive access to molecular tumor boards to support clinical decision making as well as collaborate with OmniSeq's customers to strategize on increasing enrollment of minority and underserved populations in the Gulf South community. Additionally, LSUHSC patients will have access to the OmniSeq CARES(SM) financial assistance program to help alleviate any patient out-of-pocket cost. "LSU Health New Orleans is excited to partner with OmniSeq as they provide a multifaceted approach to personalized medicine," said Dr. Augusto Ochoa, Director of LSU Health New Orleans Stanley S. Scott Cancer Center and principal investigator of a Minority Underserved National Cancer Institute Community Research Oncology Program (NCORP), funded by a grant to LSU Health New Orleans. "OmniSeq's cutting edge technology and clinical insights will improve access to precision medicine in our underserved community, offer our physicians' guidance in the development of actionable treatment plans, and help to continue to improve the standard of care for patients at LSU Health New Orleans. It will also allow NCORP investigators to design genomics-based clinical trials tailored to Louisiana and Mississippi patients." About OmniSeq OmniSeq, LLC, a CLIA licensed molecular laboratory was created from the Center for Personalized Medicine at Roswell Park Cancer Institute, an NCI-designated comprehensive cancer center in Buffalo, New York. OmniSeq is committed to improving access to the most informative molecular tumor profiling insights to help guide comprehensive cancer care. OmniSeq addresses the complete customer experience through their OmniSeq CARES(SM) Service Program which focuses on both the physician and patient by facilitating everything from sample retrieval and clinical report consultation, to insurance navigation, financial assistance and clinical trial site contacts. Headquartered in Buffalo, NY, OmniSeq offers services throughout the U.S. For more information, call 1-800-781-1259 or visit www.omniseq.com, twitter.com/OmniSeq, linkedin.com/company/omniseq-precision-medicine-technology, or facebook.com/OmniSeqComprehensive. About LSU Health New Orleans: LSU Health Sciences Center New Orleans educates Louisiana's health care professionals. The state's health university leader, LSU Health New Orleans includes a School of Medicine, the state's only School of Dentistry, Louisiana's only public School of Public Health, and Schools of Allied Health Professions, Nursing, and Graduate Studies. LSU Health New Orleans faculty takes care of patients in public and private hospitals and clinics throughout the region. In the vanguard of biosciences research in a number of areas in a worldwide arena, the LSU Health New Orleans research enterprise generates jobs and enormous economic impact. LSU Health New Orleans faculty have made lifesaving discoveries and continue to work to prevent, advance treatment, or cure disease. To learn more, visit www.lsuhsc.edu, twitter.com/LSUHealthNO or facebook.com/LSUHSC. About the GS-MU-NCORP: The Gulf South Minority Underserved National Cancer Institute Community Oncology Research Program (NCORP), led by Dr. Augusto Ochoa, is a consortium of community hospitals and/or oncology practices and integrated healthcare systems with a patient population of at least 30% racial/ethnic minorities or rural residents. It accrues participants to cancer prevention, control, screening and post-treatment surveillance clinical trials conducted by NCORP and to NCI's National Clinical Trials Network (NCTN) treatment, imaging and quality of life trials.
Narasimhan M.,Texas Tech University Health Sciences Center |
Rathinam M.,Texas Tech University Health Sciences Center |
Riar A.,Texas Tech University Health Sciences Center |
Patel D.,Texas Tech University Health Sciences Center |
And 6 more authors.
Alcoholism: Clinical and Experimental Research | Year: 2013
Background: Prenatal exposure to ethanol (EtOH) elicits a range of neuro-developmental abnormalities, microcephaly to behavioral deficits. Impaired protein synthesis has been connected to pathogenesis of EtOH-induced brain damage and abnormal neuron development. However, mechanisms underlying these impairments of protein synthesis are not known. In this study, we illustrate the effects of EtOH on programmed cell death protein 4 (PDCD4), a tumor and translation repressor. Methods: Primary cortical neurons (PCNs) were treated with 2.5 and 4 mg/ml EtOH for different time points (4 to 24 hours), and PDCD4 expression was detected by Western blotting. Protein synthesis was determined using [35S] methionine incorporation assay. Methyl cap pull-down assay was performed to establish the effect of EtOH on association of eukaryotic initiation factor 4A (eIF4A) with capped mRNA. Luciferase assay was performed to determine the in vivo translation. A 2-day acute 5-dose binge model with EtOH (4 g/kg body wt, 25% v/v) was performed in Sprague-Dawley rats at 12-hour intervals and analyzed for PDCD4, eIF4A, and eIF4A-methyl cap association. Results: EtOH increased PDCD4 expression in a time- and dose-dependent manner in PCNs, which inhibited the association of eIF4A with methyl cap. EtOH and ectopic PDCD4 expression suppressed in vivo translation in PCNs and RNAi targeting of PDCD4 blocked the inhibitory effect of EtOH on protein synthesis. In utero exposure of pregnant rats to EtOH resulted in a significant increase in PDCD4 in fetal cerebral cortex along with the inhibition of methyl cap-associated eIF4A, compared with isocaloric controls. Increased PDCD4 also occurred in pooled fractions of remaining brain regions. Conclusions: Our data, for the first time, illustrate that PDCD4 mediates inhibitory effects of EtOH on protein synthesis in PCNs and developing brain. © 2012 by the Research Society on Alcoholism.
Murray D.R.,William S Middleton Memorial Veterans Hospital |
Mummidi S.,University of Texas Health Science Center at San Antonio |
Mummidi S.,Center for Personalized Medicine |
Valente A.J.,University of Texas Health Science Center at San Antonio |
And 7 more authors.
Journal of Molecular and Cellular Cardiology | Year: 2012
Both the sympathetic nervous system and the proinflammatory cytokine interleukin-18 (IL-18) play key roles in the pathophysiology of the hypertrophied failing heart. IL-18 binding protein (IL-18BP), a natural inhibitor of IL-18, counters its biological effects. β-AR stimulation induces IL-18 expression, but whether it also regulates IL-18BP is not known. Here we demonstrate that the β-AR agonist isoproterenol (ISO) increases steady state IL-18BP mRNA and protein levels in adult mouse cardiomyocytes in a β 2-AR-dependent manner. We cloned mouse Il18bp 5'cis-regulatory region, and identified putative CREB and C/EBPβ transcription factor-binding sites. Forced expression of mutant CREB or C/EBPβ knockdown markedly attenuated ISO-induced Il18bp transcription and deletion or mutation of CREB and C/EBP motifs in the Il18bp promoter reduced ISO-induced promoter-reporter gene activity. ISO induced CREB and C/EBPβ activation in cardiomyocytes via PI3K/Akt and ERK1/2. Importantly, ISO-induced hypertrophy in vitro was dependent on IL-18 induction as it was blunted by IL-18 neutralizing antibodies and forced expression of IL-18BP. Moreover, ISO-induced hypertrophy was markedly attenuated in IL-18 null and IL-18BP transgenic mice. These data support the novel concept that β-AR activation, in addition to inducing cardiomyocyte hypertrophy via IL-18, concomitantly induces a countering effect by stimulating IL-18BP expression, and that ISO-induced cardiomyocyte hypertrophy may result from a net effect of IL-18 and IL-18BP induction. © 2011 Elsevier Ltd.
Pham M.-H.T.,Center for Personalized Medicine |
Pham M.-H.T.,University of Texas Health Science Center at San Antonio |
Bonello G.B.,Center for Personalized Medicine |
Bonello G.B.,University of Texas Health Science Center at San Antonio |
And 10 more authors.
PLoS ONE | Year: 2012
CC chemokine ligand 2 (CCL2) is the most potent monocyte chemoattractant and inter-individual differences in its expression level have been associated with genetic variants mapping to the cis-regulatory regions of the gene. An A to G polymorphism in the CCL2 enhancer region at position -2578 (rs1024611; A>G), was found in most studies to be associated with higher serum CCL2 levels and increased susceptibility to a variety of diseases such as HIV-1 associated neurological disorders, tuberculosis, and atherosclerosis. However, the precise mechanism by which rs1024611influences CCL2 expression is not known. To address this knowledge gap, we tested the hypothesis that rs1024611G polymorphism is associated with allelic expression imbalance (AEI) of CCL2. We used haplotype analysis and identified a transcribed SNP in the 3′UTR (rs13900; C>T) can serve as a proxy for the rs1024611 and demonstrated that the rs1024611G allele displayed a perfect linkage disequilibrium with rs13900T allele. Allele-specific transcript quantification in lipopolysaccharide treated PBMCs obtained from heterozygous donors showed that rs13900T allele were expressed at higher levels when compared to rs13900C allele in all the donors examined suggesting that CCL2 is subjected to AEI and that that the allele containing rs1024611G is preferentially transcribed. We also found that AEI of CCL2 is a stable trait and could be detected in newly synthesized RNA. In contrast to these in vivo findings, in vitro assays with haplotype-specific reporter constructs indicated that the haplotype bearing rs1024611G had a lower or similar transcriptional activity when compared to the haplotype containing rs1024611A. This discordance between the in vivo and in vitro expression studies suggests that the CCL2 regulatory region polymorphisms may be functioning in a complex and context-dependent manner. In summary, our studies provide strong functional evidence and a rational explanation for the phenotypic effects of the CCL2 rs1024611G allele.
Erb H.H.H.,Innsbruck Medical University |
Langlechner R.V.,Innsbruck Medical University |
Moser P.L.,Innsbruck Medical University |
Handle F.,Innsbruck Medical University |
And 8 more authors.
Endocrine-Related Cancer | Year: 2013
Development and progression of prostate cancer (PCa) are associated with chronic inflammation. The cytokine interleukin 6 (IL6) can influence progression, differentiation, survival, and angiogenesis of PCa. To identify novel pathways that are triggered by IL6, we performed a gene expression profiling of two PCa cell lines, LNCaP and MDA PCa 2b, treated with 5 ng/ml IL6. Interferon (IFN) regulatory factor 9 (IRF9) was identified as one of the most prevalent IL6-regulated genes in both cell lines. IRF9 is a mediator of type I IFN signaling and acts together with STAT1 and 2 to activate transcription of IFN-responsive genes. The IL6 regulation of IRF9 was confirmed at mRNA and protein levels by quantitative real-time PCR and western blot respectively in both cell lines and could be blocked by the anti-IL6 antibody Siltuximab. Three PCa cell lines, PC3, Du-145, and LNCaP-IL6C, with an autocrine IL6 loop displayed high expression of IRF9. A tissue microarray with 36 PCa tissues showed that IRF9 protein expression is moderately elevated in malignant areas and positively correlates with the tissue expression of IL6. Downregulation and overexpression of IRF9 provided evidence for an IFN-independent role of IRF9 in cellular proliferation of different PCa cell lines. Furthermore, expression of IRF9 was essential to mediate the antiproliferative effects of IFNa2. We concluded that IL6 is an inducer of IRF9 expression in PCa and a sensitizer for the antiproliferative effects of IFNα2. © 2013 The authors Published by Bioscientifica Ltd.
Hartsough E.M.,Center for Personalized Medicine |
Shah P.,Arizona State University |
Larsen A.C.,Center for Personalized Medicine |
Chaput J.C.,Center for Personalized Medicine |
Chaput J.C.,Arizona State University
BioTechniques | Year: 2015
Cell-free protein synthesis (CFPS) allows researchers to rapidly generate functional proteins independent of cell culture. Although advances in eukaryotic lysates have increased the amount of protein that can be produced, the nuances of different translation systems lead to variability in protein production. To help overcome this problem, we have compared the relative yield and template requirements for three commonly used commercial cell-free translation systems: wheat germ extract (WGE), rabbit reticulocyte lysate (RRL), and HeLa cell lysate (HCL). Our results provide a general guide for researchers interested in using cell-free translation to generate recombinant protein for biomedical applications. © 2015, Eaton Publishing Company. All rights reserved.
Feng J.,Center for Craniofacial Molecular Biology |
Jing J.,University of Sichuan |
Sanchez-Lara P.A.,University of Southern CaliforniaLos Angeles 90033 United States |
Bootwalla M.S.,Center for Personalized Medicine |
And 4 more authors.
Genesis | Year: 2016
Pax9 encodes a paired-box homeodomain (Pax) transcription factor and is critical for the development of multiple organs. Using CrispR/Cas9-mediated homologous directed repair (HDR), we generated a new Pax9-CreER knock-in mouse line in which the CreERT2 fusion protein is produced after synthesis of endogenous Pax9 protein. We found that tdTomato reporter expression in Pax9-CreER;tdTomato reporter mice is detectable in a similar pattern to the endogenous Pax9 expression, faithfully recapitulating the Pax9 expression domains throughout the embryo and in the adult mouse. At early embryonic stages, the tdTomato reporter is expressed first in the pharyngeal pouch region and later in the craniofacial mesenchyme, somites, limbs, and lingual papillae in the adult tongue. These results demonstrate that this new Pax9-CreER knock-in mouse line can be used for lineage tracing and genetic targeting of Pax9-expressing cells and their progeny in a temporally and spatially controlled manner during development and organogenesis. © 2016 Wiley Periodicals, Inc.
Barillari C.,Swiss Institute of Bioinformatics |
Ottoz D.S.M.,Swiss Institute of Bioinformatics |
Ottoz D.S.M.,Center for Personalized Medicine |
Fuentes-Serna J.M.,Swiss Institute of Bioinformatics |
And 3 more authors.
Bioinformatics | Year: 2015
Summary: The open-source platform openBIS (open Biology Information System) offers an Electronic Laboratory Notebook and a Laboratory Information Management System (ELN-LIMS) solution suitable for the academic life science laboratories. openBIS ELN-LIMS allows researchers to efficiently document their work, to describe materials and methods and to collect raw and analyzed data. The system comes with a user-friendly web interface where data can be added, edited, browsed and searched. Availability and implementation: The openBIS software, a user guide and a demo instance are available at https://openbis-eln-lims.ethz.ch. The demo instance contains some data from our laboratory as an example to demonstrate the possibilities of the ELN-LIMS (Ottoz et al., 2014). For rapid local testing, a VirtualBox image of the ELN-LIMS is also available. © 2015 The Author 2015. Published by Oxford University Press.
PubMed | Center for Personalized Medicine, Moscow State University, Ministry of Health of the Republic of Sakha Yakutiya, Moscow Medical Academy and Laboratory of Genomic Medicine
Type: | Journal: The International journal of risk & safety in medicine | Year: 2015
Vitamin K antagonists are effective in the prevention and treatment of thromboembolic disorders. Warfarin is one of the most widely prescribed vitamin K antagonists in the world [1, 2]. It has a narrow therapeutic range and a given dose may result in a large inter-individual variation of response. Insufficient dose may fail to prevent thromboembolism, while an overdose increases the risk of bleeding. Patient-specific factors (e.g., age, body size, race, concurrent diseases, and medications) explain some of the variability in warfarin dosage, but genetic factors influencing warfarin response explain a significantly higher proportion of this variability . Molecular analysis of the gene that encodes the target enzyme vitamin K epoxide reductase complex 1 (VKORC1) strongly suggests that its genetic variations greatly affect the individual response to oral anticoagulants [4-7].To evaluate effects of VKORC1 polymorphisms on warfarin dose excess anticoagulation (INR >4.0) in the population of Sakha (S) patients.53 patients (29-women, 24-men) with atrial fibrillation (68%), congestive heart failure (60%), hypertension (49%) and cardiac valve replacement (26%) were recruited. The age range was 26-80 years, with a mean age of 62.87 12.57 years.International normalized ratio and plasma warfarin concentrations were determined. Genotyping was carried out by RT-PCR (real-time PCR). The three genetic polymorphisms of the gene VKORC1 G3673A (rs9923231) were studied: normal (GG), heterozygous (GA) and homozygous (AA). Fisher exact probability test and chi-square test (with Yates correction) were applied to compare data among the AA and GG + GA groups; also Mann-Whitney test was used.The median maintenance daily dose of warfarin among AA carriers was 3.0 mg/day [1.25-7.5 mg], while in GG and GA patients it was 3.13 mg/day [1.88-7.92 mg]. The mean daily warfarin dosage was higher in GG and GA genotype carriers 4.05 mg/day (SD 1.7) than in patients with AA genotype 3.13 (SD 1.5). Differences are of borderline significance (p = 0.054). Of the 41 patients who required warfarin doses of less than 5 mg, 28 (63%) were found to be AA carriers and 14 (37%) were GG, GA carriers. Differences were not quite significant (p = 0.072). Among 31 homozygous polymorphism carriers 2 (4%) patients developed overanticoagulation (INR >4.0), while among 22 normal and heterozygous polymorphisms carriers only 3 (6%) patients developed overanticoagulation (INR >4.0). Differences were not statistically significant (p = 0.36).No significant association between VKORC1 polymorphisms and the frequency of excess anticoagulation (INR >4.0) was found. This may be explained by the number of cases included. AA polymorphisms compared to other polymorphisms shows borderline difference in the warfarin dose. The results can be used for the development of a pharmacogenetic-guided warfarin dosing algorithm.