title: Genes related to emphysema are enriched for ubiquitination pathways

status: Public on Nov 07 2014

city: West Point

first: I-Ming

last: Wang

state: PA

address: 770 Sumneytown Pike

department: Genetics and Pharmacogenomics

institute: Merck Research Lab

summary:
Increased small airway resistance and decreased lung elasticity contribute to the airflow limitation in chronic obstructive pulmonary disease (COPD).  The lesion that corresponds to loss of lung elasticity is emphysema; the small airway obstruction is due to inflammatory narrowing and obliteration.  Despite their convergence in altered physiology, different mechanisms contribute to these processes. The relationships between gene expression and these specific phenotypes may be more revealing than comparison with lung function. We measured the ratio of alveolar surface area to lung volume (SA/V) in lung tissue from 43 smokers.  Two samples from 21 subjects, in which SA/V differed by > 49 cm2/mL were profiled to select genes whose expression correlated with SA/V.  The level of expression of 181 transcripts was related to SA/V ( p< 0.05).   The relationship between expression of these transcripts and SA/V was tested in the 22 remaining subjects as a replication.  Thirty of the 181 genes remained significantly associated with SA/V (P<0.05) and the direction of association was the same in 164/181. Pathway and network analysis revealed enrichment of genes involved in protein ubiquitination, and western blotting showed altered expression of genes involved in protein ubiquitination in obstructed individuals. These data implicate modified protein ubiquitination and degradation as a potentially important pathway in the pathogenesis of emphysema.
Raw data not available for this study

overall_design: RNA from 8 GOLD 0 subjects (non-obstructed smokers) was pooled to form the reference to compare with each individual sample. mRNA from the specimens was profiled using the same Agilent array design (Platform: GPL3991. Human 3.0 A1 containing 23,757 probe-sets) and samples are derived from the same patient cohort as those in GSE8500 study. Since a “batch effect” confounded the results, we performed a very conservative phase/batch adjustment step before commencing with statistical analysis (information will be provided in the future online supplement).

first: Sergey

last: Stepaniants

first: Yves

last: Boie

first: James

last: Mortimer

first: Brian

last: Kennedy

first: Mark

last: Elliott

first: Shizu

last: Hayashi

first: Honglin

last: Luo

first: Jerry

last: Wong

first: Leanna

last: Loy

first: Silvija

last: Coulter

first: Christopher

middle: J

last: Roberts

last: Hogg

first: Gary

last: O’Neill

first: Michael

last: Crackower

first: Melody

last: Morris

first: Ma’en

last: Obeidat

first: Peter

middle: D

last: Paré


title: Allergic and non-allergic childhood asthma is characterized by novel gene expression profiles and signaling pathways

status: Public on Oct 01 2014

city: München

first: Olivia

last: Prazeres da Costa

state: Bavaria

address: Trogerstr. 30

department: Medical Microbiology, Immunology and Hygiene

country: Germany

institute: Technische Universität München

summary: This SuperSeries is composed of the SubSeries listed below.

overall_design: Refer to individual Series

first: Diana

last: Raedler

first: Nikolaus

last: Ballenberger

first: Elisabeth

last: Klucker

first: Andreas

last: Böck

first: Julia

last: Roeb

first: Erika

last: von Mutius

first: Thorsten

last: Buch

first: Ulrich

last: Mansmann

first: Bianca

last: Schaub


title: Gene expression data from CD4pos human childhood study

summary: Reveal differentially regulated genes and cellular pathways within allergic and non-allergic asthmatic children compared to healthy controls

overall_design: CD4pos cells were obtained from allergic asthmatics, non-allergic asthmatics and healthy controls and kept without stimulation.


title: Gene expression data from PBMCs human childhood study

overall_design: Peripheral blood mononuclear cells (PBMCs) were obtained from allergic asthmatics (n=14), non-allergic asthmatics (n=8) and healthy controls (n=14) and kept with anti-CD3/CD28 (CD328), LpA or without stimulation (M).


title: Molecular profiling of peripheral blood is associated with circulating tumor cells content and poor survival in metastatic castration-resistant prostate cancer

status: Public on Apr 30 2015

city: Barcelona

first: Juanjo

last: Lozano

address: C/ Rosselló 153

department: Plataforma de Bioinformatica

country: Spain

institute: CIBEREHD

summary: The enumeration of circulating tumor cells (CTCs) in peripheral blood correlates with clinical outcome in castration-resistant prostate cancer (CRPC). We analyzed the molecular profiling of peripheral blood from 43 metastatic CRPC patients with known CTC content in order to identify genes that may be related to prostate cancer progression. Global gene expression analysis identified the differential expression of 282 genes between samples with ≥5 CTCs vs <5 CTCs, 58.6% of which were previously described as over-expressed in prostate cancer (18.9% in primary tumors and 56.1% in metastasis). Those genes were involved in survival functions such as metabolism, signal transduction, gene expression, and cell growth, death, and movement. The expression of selected genes was evaluated by quantitative RT-PCR. This analysis revealed a two-gene model (SELENBP1 and MMP9) with a high significant prognostic ability (HR 6; 95% CI 2.61 - 13.79; P<0.0001). The combination of the two-gene signature plus the CTCs count showed a higher prognostic ability than neither CTCs enumeration nor gene expression alone (P<0.05). This study shows a gene expression profile in PBMNC is associated with CTCs count and clinical outcome in metastatic CRPC, describing genes and pathways potentially associated with CRPC progression.

overall_design: The complete database comprised the expression measurements of 43 metastatic castration-resistant prostate cancer (CRPC) samples and their asociation with the number of circulating tumor cells (CTCs). Twenty of them have a  number circulating tumor cells (CTCs) greater than 5.

first: M

last: Marin-Aguilera

first: O

last: Reig

first: J

first: B

last: Mellado


title: Copy number profile of human prostate cancer organoid lines using Agilent 1M aCGH platform

status: Public on Sep 09 2014

city: New York

first: Yu

last: Chen

state: NY

address: 1275 York Ave, Box 20

department: Human Oncology and Pathogenesis Program

country: USA

institute: Memorial Sloan Kettering Cancer Center

type: Genome variation profiling by genome tiling array

summary: Advanced prostate cancer is a highly heterogenous disease with few in vitro models. We report generation of seven novel 3D organoid lines of patient-derived prostate cancer. We determine the copy number alterations of these lines using array CGH. They contain may classic alterations of prostate cancer such as lost of the short arm of chromosome 8 and gain of the long arm of chromosome 8. In addition, we found homozygous deleteion of tumor suppressor PTEN and CHD1 as well as the TMPRSS2-ERG interstitial deletion.

overall_design: Prostate cancer organoid lines, ~2 months after in vitro propagation, were used for profiling  on Agilent 1M aCGH arrays per manufacturer's instructions. A pooled reference normal DNA was used as the reference.

first: Dong

last: Gao


title: Expression data from 48 h incubation of RAW264.7 cells with 50 ng/ml RANK Ligand

status: Public on Nov 11 2015

city: Indianapolis

first: Andy

state: IN

address: 410 W 10th Street, Suite 5000

department: MMGE

institute: IUSM

summary:
A variety of genes are responsible for regulating osteoclastogenesis in response to RANK Ligand.
Microarray analysis was used to identify genes sensitive to RANKL-induced osteoclastogenesis in RAW264.7 cells.

overall_design: RAW264.7 cells were incubated with 50 ng/mL RANKL or vehicle control (3 replicates each).  After 48 h, total RNA were harvested by an RNeasy Plus Mini Kit (QIAGEN).

first: Kazunori

last: Hamamura

first: Shinya

last: Takigawa

middle: B

first: Hiroki

last: Yokota


title: Effects of Beta Catenin antagonist BC2059 in AML cells

status: Public on Dec 31 2014

city: Houston

first: Kapil

last: Bhalla

state: TX

address: 1400 Holcombe Blvd., Unit 428

institute: MD Anderson Cancer Center

summary:
To determine the global transcriptomic changes induced by treatment with the Beta Catenin antagonist BC2059 in AML cells
The canonical WNT-β-catenin pathway is essential for self-renewal, growth and survival of AML stem/blast progenitor cells (BPCs). Deregulated WNT signaling inhibits degradation of β-catenin, causing increased nuclear translocation and co-factor activity of β-catenin with the transcriptional regulator TCF4/LEF1 in AML BPCs. Here, we determined the pre-clinical anti-AML activity of the anthraquinone oxime-analog BC2059 (BC), known to attenuate β-catenin levels. BC treatment disrupted the binding of β-catenin with the scaffold protein TBL1 (transducin β-like 1) and proteasomal degradation and decline in the nuclear levels of β-catenin. This was associated with reduced transcriptional activity of TCF4 and expression of its target genes, cyclin D1, c-Myc and survivin. BC treatment dose-dependently induced apoptosis of cultured and primary AML BPCs. Treatment with BC also significantly improved the median survival of immune-depleted mice engrafted with either cultured or primary AML BPCs exhibiting nuclear expression of β-catenin. Co-treatment with the pan-histone deacetylase inhibitor panobinostat and BC synergistically induced apoptosis of cultured and primary AML BPCs, including those expressing FLT3-ITD, as well as further significantly improved the survival of immune-depleted mice engrafted with primary AML BPCs. These findings underscore the promising pre-clinical activity and warrant further testing of BC against human AML, especially those expressing FLT3-ITD.

overall_design: 4 samples analyzed: OCI-AML3 cells (untreated); OCI-AML3 cells treated with 100 nM of BC2059 for 8 hours; Primary FLT3-ITD expressing AML cells (untreated);  Primary FLT3-ITD expressing AML cells treated with 100 nM of BC2059 for 8 hours.

middle: N

first: Warren

last: Fiskus


title: H3K4me1 marks DNA regions hypomethylated during aging in human stem and differentiated cells [MSCs]

status: Public on Sep 25 2014

city: Oviedo

first: Agustin

middle: F

last: Fernandez

email: affernandez@hca.es, agusff@gmail.com

state: Asturias

address: Avenida de Roma s/n

department: IUOPA

institute: Oviedo University-HUCA

summary: In differentiated cells, aging is associated with hypermethylation of DNA regions enriched in repressive histone posttranslational modifications. However, the chromatin marks associated with changes in DNA methylation in adult stem cells during lifetime are still largely unknown. Here, DNA methylation profiling of mesenchymal stem cells obtained from individuals aged 2 to 92 identified 18735 hypermethylated and 45407 hypomethylated CpG sites associated with aging. As in differentiated cells, hypermethylated sequences were enriched in chromatin repressive marks. Most importantly, hypomethylated CpG sites were strongly enriched in the active chromatin mark H3K4me1 in stem and differentiated cells, suggesting this is a cell type-independent chromatin signature of DNA hypomethylation during aging. Analysis of scedasticity showed that interindividual variability of DNA methylation increased during aging in MSCs and differentiated cells, providing a new avenue for the identification of DNA methylation changes over time. DNA methylation profiling of genetically identical individuals showed that both the tendency of DNA methylation changes and scedasticity depended on non-genetic as well as genetic factors. Our results indicate that the dynamics of DNA methylation during aging depend on a complex mixture of factors that include the DNA sequence, cell type and chromatin context involved, and that, depending on the locus, the changes can be modulated by genetic and/or external factors.

overall_design: Total DNA isolated by standard procedures from human adult mesenchymal stem cells (MSCs) obtained from 34 individuals aged 2 to 92

first: Gustavo

last: Bayón

first: Rocío

middle: G

last: Urdinguio

first: Estela

last: Toraño

first: Maria

last: Garcia

first: Antonella

last: Carella

first: Sandra

last: Petrus-Reurer

first: Cecilia

last: Ferrero

first: Pablo

last: Martinez-Camblor

first: Isabel

last: Cubillo

first: Javier

last: García-Castro

first: Jesús

last: Delgado-Calle

first: Flor

middle: M

last: Perez-Campo

first: José

middle: A

last: Riancho

first: Clara

last: Bueno

last: Menendez

first: Anouk

last: Mentink

first: Katia

last: Mareschi

first: Fabian

last: Claire

first: Corrado

last: Fagnani

first: Emanuela

last: Medda

first: Virgilia

last: Toccaceli

first: Sonia

last: Brescianini

first: Sebastián

last: Moran

first: Manel

last: Esteller

first: Alexandra

last: Stolzing

first: Jan

last: de Boer

first: Lorenza

last: Nisticò

last: Stazi

first: Mario

last: Fraga


title: H3K4me1 marks DNA regions hypomethylated during aging in human stem and differentiated cells

first: Agustin

last: Fernandez


title: Role of Jmjd2b and Jmjd2c in mESCs identity

status: Public on Dec 01 2013

city: Shanghai

first: Zhen

last: Shao

address: 320 Yueyang Road

country: China

institute: Partner Institute for Computational Biology, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences

summary: We used microarray to determine the changes in gene expression profile after KD of Jmjd2b and Jmjd2c compared to Anti-GFP KD from mES cells

overall_design: Mouse ES cells were infected with AntiGFP, Jmjd2b and Jmjd2c shRNAs lentivirus, puromycin selected, passage them 2-3 times, collected for RNA isolation and gene expression

first: Partha

middle: P

last: Das

first: Stuart

middle: H

last: Orkin


title: Expression analysis of stable chronic obstructive pulmonary disease and acute exacerbation of chronic obstructive pulmonary disease

status: Public on Aug 14 2014

city: ShangHai

first: Wang

last: Xiangdong

address: Fenglin Road No.180

institute: Zhongshan Hospital

summary: Investigation of whole genome gene expression level changes of the dynamic gene profiling of peripheral blood mononuclear cells (PBMCs) from patients with AECOPD) on day1, 3 and 10, compared to the normal people and stable COPD patients.

overall_design: A five chip study using total RNA recovered from Peripheral Blood Mononuclear Cell of Peripheral Blood.Evaluating the dynamic gene profiling of peripheral blood mononuclear cells (PBMCs) from patients with AECOPD) on day1, 3 and 10 after the hospital admission, to compared with healthy controls or patients with stable COPD. Slides were scanned at 5 μm/pixel resolution using an Axon GenePix 4000B scanner (Molecular Devices Corporation) piloted by GenePix Pro 6.0 software (Axon). Scanned images (TIFF format) were then imported into NimbleScan software (version 2.5) for grid alignment and expression data analysis. Expression data were normalized through quantile normalization and the Robust Multichip Average (RMA) algorithm included in the NimbleScan software. The Probe level (*_norm_RMA.pair) files and Gene level (*_RMA.calls) files were generated after normalization.

first: Xiangdong

last: Wang

first: Xiaodan

last: Wu


title: Downregulation of micro RNAs 145-3p and 145-5p is a Long-Term Predictor of Postmenopausal Breast Cancer Risk: the ORDET prospective study

status: Public on Sep 10 2014

city: rome

first: andrea

last: sacconi

address: via elio chianesi

country: Italy

institute: regina elena cancer institute

summary: microRNA expression profile of buffy coat derived from healty woman before the insorgence of breast cancer

overall_design: microRNA expression was evaluated from total RNA extracted from buffy coat.

first: Andrea

last: Sacconi

first: Giovanni

last: Blandino

first: Paola

last: Muti


title: Expression data from human primary fibroblasts (IMR90) stably expressing H-RasV12 and shRNA against ERK2 or a non-targeting shRNA

city: Montréal

first: Xavier

last: Deschênes-Simard

state: Québec

address: 3655 Sir William Osler

department: Medicine

country: Canada

institute: McGill University

summary:
Oncogenic ras activates several signaling pathways that cooperate in cell transformation. They include the ERK/MAP kinase pathway, the PI3K pathway and the Ral pathway among others. Surprisingly, in primary human fibroblasts, oncogenic ras expression induces senescence not transformation, but upon knockdown of ERK2 senescence is bypassed and transformation is stimulated.
We used microarrays to characterize the gene expression programme of cells transformed by oncogenic ras, telomerase and knockdown of the ERK2 kinase.

overall_design: Primary human fibroblasts were co-infected with a retroviral vector that expresses oncogenic ras and either a control shRNA or an shRNA against ERK2. Cells with oncogenic ras and shRNA control entered senescence while cells with oncogenic ras and shRNA ERK2 bypassed senescence and underwent malignant transformation. Triplicates of these populations were used to purify total RNA, which we sent to Genome Quebec service for hybridization with Affymetrix microarrays.

first: Véronique

last: Bourdeau

first: Marie-France

last: Gaumont-Leclerc

first: Gerardo

last: Ferbeyre


title: Absolute and induction TNF tolerance in primary human monocytes

status: Public on Feb 11 2014

city: Hannover

first: Oliver

last: Dittrich-Breiholz

address: Carl-Neuberg-Str. 1

department: Research Core Unit Genomics

institute: Medical School Hannover

summary: The molecular basis of TNF tolerance is poorly understood. In this experiment, primary human monocytes were used to examine TNF refractoriness. We detect absolute tolerance as  selective, dose-dependently affecting a small group of powerful effector molecules; induction tolerance represented a more general phenomenon.

overall_design: Primary human monocytes were incubated for 48 h with Medium or different TNF-doses and subsequently short-term stimulated for two hours with TNF. Total RNA was prepared and analysed by use of Agilent microarrays. 6 different conditions were analyzed in total, corresponding to cells that were: 1) medium incubated (M+M), 2) medium incubated and short time TNF (400 U/ml) incubated (M+T), 3) low dose TNF (40 U/ml) preincubated (40+M), 4) low dose TNF preincubated and short time TNF incubated (40+T), 5) high dose TNF (400 U/ml) preincubated (400+M), 6) high dose TNF preincubated and short time TNF incubated (400+T). 3 biological replicates (corresponding to three different healthy donors) were analyzed regarding high-dose tolerance conditions (preincubation with 400 U TNF/ml), one of which was analyzed in duplicates (including cell culture, RNA preparation and a dye-swap microarray approach). 2 biological replicates (corresponding to two different healthy donors) were analyzed under low-dose tolerance conditions (preincubation with 40 U/ml). The different human donors were numbered and indicated in brackets (d1-d5).

first: Johannes

last: Günter

first: Nico

last: Vogt

first: Katharina

last: Hampel

first: Rolf

last: Bikker

first: Sharon

last: Page

first: Benjamin

last: Müller

first: Judith

last: Kandemir

first: Michael

last: Kracht

first: Rene

last: Huber

first: Korbinian

last: Brand


title: Expression data from PC3 cocultured with Osteoblasts

status: Public on Apr 08 2014

city: Livermore

first: Gabriela

last: Loots

state: CA

address: 7000 East Avenue

department: Biosciences and Biotechnology Division

institute: Lawrence Livermore National Laboratory

summary: Inhibitors of Wnt signaling have been previously shown to be involved in prostate cancer (PC) metastasis; however the role of Sclerostin (Sost) has not yet been explored. Here we show that elevated Wnt signaling derived from Sost deficient osteoblasts (OBSOSTKO) promotes PC invasion while rhSOST has an inhibitory effect. In contrast, rhDKK1 promotes PC elongation and filopodia formation, morphological changes characteristic of an invasive phenotype. Furthermore, rhDKK1 was found to activate canonical Wnt signaling in PC3 cells as quantified by TOPFLASH reporter and b-catenin activity, suggesting that SOST and DKK1 have opposing roles on Wnt signaling in this context. Gene expression analysis of PC3 cells co-cultured with OBs exhibiting varying amounts of Wnt signaling identified CRIM1 as one of the transcripts up-regulated under highly invasive conditions. Following further analysis we found that CRIM1 increases PC3 invasion, complexes with b-catenin, and promotes cell-adhesion, suggesting that elevated Wnt signaling secreted from the bone may promote PC tropism by promoting CRIM1 expression and facilitating cancer cell invasion and adhesion to bone. We concluded that SOST and DKK1 have opposing effects on PC3 cell invasion and that bone-derived Wnt signaling positively contributes to the invasive phenotypes of metastatic cancer cells by activating CRIM1 expression and facilitating PC-OB physical interaction. As such, we investigated the effects of high concentrations of SOST in vivo. We found that PC3-cells overexpressing SOST injected via tail vein did not readily metastasize in NSG xenografts, suggesting that targeting the molecular bone environment may influence bone metastatic outcome in clinical settings.

overall_design: PC3 cells were cultured for 48 hours in specified conditions prior to RNA extraction and hybridization on Affymetrix Human Genome U133 Plus 2.0 Array. All experiments were performed in at least duplicates. Total RNA was collected from PC3 cells cultured in normal growth media, cocultured with WT mouse osteoblasts supplemented with recombinant human DKK1, cells cocultured with WT mouse osteoblasts supplemented with recombinant human SOST, or cocultured with SostKO mouse osteoblasts.

first: Loots

last: Gabriela

first: Hudson

last: Bryan

first: Hum

middle: R

last: Nicholas

first: Thomas

last: Cynthia

first: Kohlgruber

last: Ayano

first: Sebastian

last: Aimy

first: Coleman

last: Matthew


title: MicroRNAs Implicated in Dysregulation of Gene Expression Following Human Lung Transplantation

status: Public on Jul 20 2014

city: Reno

first: Tong

last: Zhou

state: NV

address: 1664 N Virginia St

institute: University of Nevada School of Medicine

summary: Lung transplantation remains the only viable treatment option for the majority of patients with advanced lung diseases. However, 5-year post-transplant survival rates remain low primarily secondary to chronic rejection.  Novel insights from global gene expression profiles may provide molecular phenotypes and therapeutic targets to improve outcomes after lung transplantation. We compared whole-genome transcriptional expression profiled using the Affymetrix Human Exon Array in peripheral blood mononuclear cells (PBMCs) in lung transplant patients and normal individuals. 364 dysregulated genes in Caucasian lung transplant patients relative to normal individuals. Enriched Gene Ontology biological processes and pathways included defense response, immune response” and response to wounding”. We then compared the expression profiles of potential regulating miRNAs which suggested that dysregulation of a number of lung transplant-associated genes (e.g., ATR, FUT8, LRRC8B, NFKBIA) may be attributed to the differential expression of their regulating miRNAs. This exploratory analysis of the relationship between these miRNAs and their gene targets in the context of lung transplantation warrants further investigation and may serve as novel therapeutic targets in lung transplant complications.

overall_design: PBMC samples were collected from 18 patients (14 Caucasian Americans and 4 African Americans) who underwent single-lung transplant or bilateral single-lung transplant surgery during 2005-2008. Control samples were collected from healthy individuals (27 Caucasians and 8 African Americans). Whole-genome expression profiles were performed using the Affymetrix Human Exon 1.0ST Array. The expression levels of miRNAs were profiled using the Exiqon miRCURY™0.  *This represents the Affymetrix Human Exon component of the study only.

first: Wei

last: Zhang

first: Robert

last: Machado

first: Sangeeta

last: Bhorade

first: Joe

last: Garcia


title: miRNA changes in mild and moderate emphysema correlate with target gene expression in vivo and in vitro [target gene expression data]

status: Public on Jun 01 2012

city: brisbane

first: santiyagu

middle: mary

last: savarimuthu francis

address: lvl 1, clinical sciences building, rode road, chermside

department: Thoracic Medicine

country: Australia

institute: The Prince Charles Hospital

summary: To define the role of microRNAs and their mRNA targets in emphysema severity in COPD patients.

overall_design: We performed Agilent human miRNA oligo arrays (8x15K array, Part No. G4470A, Agilent Technologies) based on miRBase V9.1 on lung tissues from 9 mild and 20 moderate emphysema lungs obtained from patients undergoing curative resection for lung cancer. We identified 5 miRNAs and two of those were tested and validated technically using qRT-PCR. The predicted mRNA targets for the five miRNAs were identified in MSigDB using GSEA and their expression were negatively correlated in exvivo lung mRNA expression profile obtained from GEO datasets (GSE17770 and GSE1650). Increasing the expression of one of the miRNA target, miR-34c in BEAS-2B and HFL 1 cell lines resulted in the downregulation of 50 TargetScan and Pictar predicted targets of miR-34c.

first: Santiyagu

last: Francis

first: Morgan

last: Davidson

first: Maxine

middle: E

last: Tan

first: Casey

last: Wright

first: Belinda

last: Clarke

first: Edwina

last: Duhig

first: Rayleen

middle: V

last: Bowman

first: Nicholas

middle: K

last: Hayward

first: Kwun

last: Fong

first: Ian

last: Yang


title: IL-6R identifies early differentiated human effector memory CD8+ T cells that potently expand and produce IL-2 and IL-13

status: Public on Dec 31 2012

city: LA

first: Sungyong

last: You

address: Beverly Blvd 8400

department: Surgery

institute: Cedars-Sinai Medical Center

summary: We found a unique subset of effector memory (EM) CD8+ T cells that expressed high levels of IL-6 receptor in human peripheral blood.  These cells which also expressed high levels of IL-7Ra (referred to as IL-6R high IL-7Rahigh cells) had the a distinct gene expression profile and cellular characteristics compared to other EM CD8+ T cells.  IL-6R high IL-7Ra high cells were early differentiated EM CD8+ T cells with decreased expression of T-bet, KLRG1, perforin and granzyme B.  These cells had increased cell proliferation likely secondary to enhanced IL-2 production and high affinity IL-2R expression.  IL-6R high IL-7Ra high EM CD8+ T cells exclusively produced high levels of IL-2, IL-5, IL-9 and IL-13 although IFN-r was produced by this cell subset and other EM CD8+ T cells.  Of interest,  IL-6R high IL-7Ra high EM CD8+ T cells expanded in the peripheral blood of patients with chronic obstructive pulmonary disease (COPD) and asthma where CD8+ T cells, IL-13 and IFN-r are suggested to be involved in the pathogenesis.  Being the early-differentiated EM CD8+ T cells with a potent capacity to proliferate, survive and generate multiple cytokines, IL-6R high IL-7Ra high EM CD8+ T cells may serve as a primary reservoir for effector CD8+ T cells which potently expand and produce cytokines upon immune stimulation.

overall_design: Duplicate experiments were performed for each condition. In each condition, we independently prepared total RNA using the RNeasy mini kit (Qiagen) and assessed RNA integrity using Bioanalyzer 2100 (Agilent)- RINs were close to 10 for all samples. RNA was then amplified and hybridized to the Illumina HumanHT-12 v4.0 BeadChip, according to Illumina standard protocols.

first: Insoo

last: Kang

first: Daehee

last: Hwang


title: The inflammatory response of human airway smooth muscle cells

status: Public on May 01 2013

city: Bochum

first: Jurgen

last: Knobloch

address: Bürkle-De-La-Camp-Platz 1

department: Medical Clinic III

institute: University Hospital Bergmannsheil

summary: Background: Tissue remodeling induced by airway inflammation is a main trigger of pathogenesis in various chronic lung diseases like asthma, COPD, IPF, and pulmonary hypertension. The role of human airway smooth muscle cells (HASMCs) in this context is unclear.  Hypothesis: HASMCs participate in linking inflammation with remodeling.  Methods: The inflammatory responses of ex vivo-cultivated HASMCs to TNFα were investigated by whole-genome-microarray analyses. Diferrential regulation of genes associated with airway inflammation and remodeling were verified by qRT-PCR and ELISA.    Results: TNFa induced the expression of 18 cytokines/chemokines and five tissue remodeling genes involved in (severe/corticosteroid-insensitive) asthma, COPD, IPF and/or pulmonary hypertension.  Conclusion: HASMCs participate in the interaction of inflammation and tissue remodeling. HASMCs might be considered as targets in therapies of chronic inflammatory lung diseases with regard to attenuating inflammation-induced remodeling processes leading to the development of emphysema or fibrosis.

overall_design: HASMCs of eight donors were left untreated of were stimulated with TNFa at 20 ng/ml. Total RNA was subjected after eight hours of stimulation to whole-human-genome oligo microarray analysis.

first: Andrea

last: Koch


title: Analysis of TLS activity in PGC-1alpha+/+ and PGC-1alpha-/- hepatocytes

status: Public on Jul 26 2013

city: Madrid

first: Maria

last: Monsalve

address: Melchor Fernandez Almagro

institute: CNIC

summary: We found that TLS can work as a PGC-1alpha cofactor and this assay was carried out to test the functional dependency of TLS on PGC-1alpha on a whole genome scale

overall_design: Three independently-isolated cultures of primary hepatocytes from PGC-1α+/+ and PGC-1α-/- mice were infected with shTLS or control adenovirus. RNA was extracted by Trizol extraction, re-purified with RNAeasy (Invitrogen), and checked for integrity and quantity with the Agilent Bio-Analyzer QC. RNA was amplified and labeled with the One-Color Microarray-Based Gene Expression Analysis Protocol (Agilent Technologies, Palo Alto, CA, USA). Samples were hybridized to a G4122F 4x44K whole mouse genome microarray (Agilent Technologies). Arrays were scanned at 5 mm resolution with a G2565BA DNA microarray scanner (Agilent Technologies) at the default settings for 4x44k format one-color arrays. Images were analyzed using Feature Extraction software v10.1.1.1 (Agilent Technologies). Raw signals were thresholded to 1 and normalized by quantile (Bolstad et al., 2003) was performed using GeneSpring software. Data were analyzed on the log2 scale. Default flags were considered as absent, except for saturated spots that were flagged as marginal.

first: Cristina

last: Sanchez-Ramos

first: Alberto

last: Tierrez

first: Oscar

last: Fabregat

first: Brigitte

last: Wild

first: Fatima

last: Sanchez-Cabo

first: Alessandro

last: Arduini

first: Ana

last: Dopazo


title: Determining the Program of Leydig Cell Development

status: Public on Dec 28 2011

city: Cambridge

first: Scott

last: Jelinsky

state: MA

address: 610 Main Street

department: Inflammation and Immunology

institute: Pfizer

summary: In the present study, microarray analysis was performed on RNA isolated from purified SLCs, PLCs, ILCs, ALCs and bone stem cells, using Affymetrix Rat Genome RAE230 2.0 arrays which monitor ~30,000 transcripts from over ~28,000 well-substantiated genes.  The focus is on the differences and similarities between SLCs and bone stem cells, and between SLCs and PLCs, ILCs and ALCs

overall_design: 3-4 replicas of leydig cells from different developmental stages were collected and analyzed


title: The Molecular Toxicity Identification Evaluation (mTIE) Approach Predicts Chemical Exposure in Daphnia magna

status: Public on Jan 17 2013

city: Liverpool

first: Philipp

last: Antczak

state: Merseyside

address: Crown Street

country: United Kingdom

institute: University of Liverpool

summary: Daphnia magna is a bio-indicator organism accepted by several international water quality regulatory agencies.  Current approaches for assessment of water quality rely on acute and chronic toxicity that provide no insight into the cause of toxicity. Recently, molecular approaches, such as genome wide gene expression responses, are enabling an alternative mechanism based approach to toxicity assessment. While these genomic methods are providing important mechanistic insight into toxicity, statistically robust prediction systems that allow the identification of chemical contaminants from the molecular response to exposure are needed. Here we apply advanced machine learning approaches to develop predictive models of contaminant exposure using a D. magna gene expression dataset for 36 chemical exposures. We demonstrate here that we can discriminate between chemicals belonging to different chemical classes including endocrine disruptors, metals and industrial chemicals based on gene expression.  We also show that predictive models based on indices of whole pathway transcriptional activity can achieve comparable results while facilitating biological interpretability.

overall_design: D. magna were exposed to 36 Chemicals and 5 control series in quadruplicate.

first: Hun

last: Je Jo

first: Seonock

last: Woo

first: Leona

last: Scanlan

first: Helen

last: Poynton

first: Alex

last: Loguinov

first: Sarah

last: Chan

first: Francesco

last: Falciani

first: Chris

last: Vulpe


title: miRNA changes in mild and moderate emphysema correlate with target gene expression in vivo and in vitro

first: santiyagu

last: savarimuthu francis

type:
Non-coding RNA profiling by array
Expression profiling by array

summary: This SuperSeries is composed of the SubSeries listed below.

overall_design: Refer to individual Series


title: Microarray profiling of rectal tumor samples

status: Public on Jan 03 2014

city: Granada

first: Carlos

last: Cano

address: Periodista Daniel Saucedo Aranda S.N.

institute: University of Granada

summary: Using Human WG CodeLink microarrays, we established the expression profiling of 26 LARC without metastasis to gain insight into the molecular signatures associated with response to treatment after CRT.

overall_design:
The study initially included a total of 35 consecutive patients with locally advanced rectal cancer (LARC) treated at Virgen de las Nieves Hospital from 2008 until 2010. Written informed consent was obtained from all the patients, and the study protocol was approved by the local Clinical Research (Ethics) Committee. They were distributed in two subgroups following a histological classification of response to treatment. Pretherapeutic staging was performed, including complete medical history and physical evaluation, digital rectal examination, endorectal ultrasound, rigid rectoscopy, colonoscopy, PET/TC and chest x-ray. Tumor samples were prospectively obtained during the rectoscopy. All patients subsequently received a total dose of 50.4Gy of radiatio (28 fractions of 1.8Gy) associated with capecitabine or capecitabine  and oxaliplatine. Standardized surgery was performed, including total mesorectal excision, after an interval of 8 weeks after chemoradiotherapy.  Tumor response was assessed in surgical specimen by semi-quantitative pathological examination (regression grade) including UICC stage. Histopathological tumor regression was graded based on the semiquantitative 5 point tumor regression grading (TRG) system: TRG1 or a TRG2 scores were considered Responders, whereas TRG3, TRG4, and TRG5 scores were classified as Non-Responders. In addition, the tumor regression or radiotherapy effects were assessed by positron emission tomography (18F-FDG PET). Tumor samples of LARC were collected from 35 patients. Nine patients were finally excluded due to the poor quality of the RNA or contradictory results of Mandard´s criteria and histopathological downstaging, resulting a total of 26 patients.
Complete clinical data regarding, age, sex, stage of disease, response to therapy, and overall survival from 26 patients (10 responders and 16 non-responders) was provided in the sample characteristics field.

CRT: Chemoradiation; Cap: Capecitabine; Capox: Capecitabine and Oxaliplatine; cTN: clinical stage; Surg: surgical technique; LAR: Low anterior resection; APR: Abdmino-perineal resection; HART: Hartmann, TRG: Tumor Regression Grade; Downst: Downstaging; Downs: downsizing, Resp: response, CPR: complete pathologic response

first: P

last: Palma

first: M

last: Cuadros


title: Blood based gene expression signature for diagnosis of epithelial ovarian cancer

status: Public on Sep 02 2011

city: Vienna

first: Dietmar

last: Pils

address: Waehringer Guertel 18-20

department: Dept. of Surgery

country: Austria

institute: Medical University of Vienna

summary: Objective: The immune system is a key player in fighting cancer. Thus, we seeked to identify a molecular ‘immune response signature’ indicating the presence of epithelial ovarian cancer (EOC) and to combine this with a serum protein biomarker panel to increase the specificity and sensitivity for earlier detection of EOC.  Methods: Comparing the expression of 32,000 genes in a leukocytes fraction from 48 EOC patients and 20 controls, three uncorrelated shrunken centroid models were selected, comprised of 7, 14, and 6 genes. A second selection step using RT-qPCR data and significance analysis of microarrays yielded 13 genes which were finally used in 343 samples (90 healthy, 6 cystadenoma, 8 low malignant potential tumor, and 239 EOC patients). Using new 65 controls and 224 EOC patients the abundances of six plasma proteins was determined and used in combination with the expression values from the 13 genes for diagnosis of EOC.   Results: Combined diagnostic models using either each five gene expression and plasma protein abundance values or 13 gene expression and six plasma protein abundance values can discriminate controls from patients with EOC with Receiver Operator Characteristics Area Under the Curve values of 0.998 and bootstrap .632+ validated classification errors of 3.1% and 2.8%, respectively. The sensitivities were 97.8% and 95.6%, respectively, at a set specificity of 99.6%.  Conclusion: The combination of expression based and plasma protein based biomarkers in one diagnostic model increases the sensitivity and the specificity significantly. Such a diagnostic test may allow earlier diagnosis of epithelial ovarian cancer.

overall_design: The expression of a blood cell fraction from 20 healthy controls and 48 patients with epithelial ovarian cancer was compared.

first: Dan

last: Cacsire Castillo-Tong

first: Robert

last: Zeillinger


title: Development of microRNA expression signature for emphysema in COPD patients

first: Santiyagu

last: Francis

first: Morgan

last: Davidson

first: Maxine

last: Tan

first: Casey

last: Wright

first: Belinda

last: Clarke

first: Edwina

last: Duhig

first: Rayleen

last: Bowman

first: Nicholas

last: Hayward

first: Kwun

last: Fong

first: Ian

last: Yang


title: Comparative Genome Analysis of Ureaplasma parvum Clinical Isolates

status: Public on Jul 25 2006

city: Moscow

first: Andrew

middle: Victorovich

last: Klubin

address: ul. Malaya Pirogovskaya 1a

department: Departament of molecular biology and genetics

country: Russia

institute: Research Institute of  Physico-Chemical Medicine

summary:
Ureaplasma are widespread parasites colonizing the mucosal surface of the human urogenital tract, and it has been suspected as a causative agent of nongonococcal urethritis, pregnancy complications and prenatal infections. Ureaplasma may also cause central nervous system infections and affect the lower respiratory tract of newborn babies. However, Ureaplasma spp. have also been detected in the urogenital tracts of clinically healthy patients, and their role in the development of infections thus remains unclear. Like in other organisms, virulence of Ureaplasma is determined by the presence of virulence factors - adhesions, human IgA protease, phospholipase and urease. However, the existence of interrelationships between the presence of these genes in the Ureaplasma genome and the incidence of diseases in man has not been demonstrated. Difficulties in the elucidation of these interrelationships may arise from significant macro- (gene mutation, chromosomal rearrangements) and micro- (nucleotide polymorphism) genomic heterogeneity. It is possible that the combination of the variable strain-specific genes in Ureaplasma with generally known virulence factors determine the development of pathological processes on the mucosal surface of the human urogenital tract.
Keywords: macroarray, variability of genome, Ureaplasma parvum

overall_design: In our research we used 10 clinical and 1 laboratory strain

first: Kuvat

middle: T

last: Momynaliev

first: Vera

last: Chelysheva

first: Oksana

last: Selesneva

first: Tatyana

last: Akopian

first: Vadim

last: Govorun


title: Bile acids promote adenocarcinoma in a novel transgenic mouse model of Barrett’s esophagus

status: Public on Jan 31 2011

city: München

first: Michael

last: Quante

address: Ismaninger Str 22

department: II Medizinische Klinik

institute: Technische Universität München

summary: Esophageal adenocarcinoma (EAC) has the fastest increase of any cancer in the US and Europe, and arises in the setting of Barrett’s esophagus (BE),  defined by replacement of normal squamous epithelium with columnar intestinal-like epithelium. BE is thought to result from chronic esophageal inflammation but has been elusive to model in animals. Herein, we have generated the first transgenic mouse model of Barrett’s esophagus through overexpression of interleukin-1ß (IL-1β).  IL-1β overexpression in the mouse esophageal mucosa induces chronic inflammation that progresses to intestinal metaplasia, with characteristic expression of TFF2, Bmp4 and Cdx2. With aging, IL-1b transgenic mice progress to esophageal adenocarcinoma (EAC) but the process is markedly accelerated by exposure to bile acids and/or nitrosamines, resembling the human counterpart. Moreover, progenitor cells present in the gastric cardia, but absent from the esophagus in humans and mice, are increased in BE, suggesting the cell of origin in the gastric cardia

overall_design: Comparison of BE and EAC tissue from the mouse with normal squamous epithelium from the mouse.

first: Govind

last: Bhagat

first: Julian

last: Abrams

first: Frederic

last: Marache

first: Pamela

last: Good

first: Michele

last: Lee

first: Umar

last: Mahmood

first: Jose-Luiz

last: Figueiredo

first: Charles

last: Lightdale

first: Anil

last: Rustgi

first: Richard

last: Friedman

first: Timothy

middle: C

last: Wang


title: Genome-wide analysis of PHABULOSA targets in Arabidopsis root meristem

city: Ithaca

first: Ji-Young

address: Tower Rd.

institute: Boyce Thompson Institute

type: Expression profiling by genome tiling array

summary: We report the discovery of a root growth program in Arabidopsis that is independent of a functional quiescent center (QC). In this regulatory program, PHABULOSA (PHB), posttranscriptionally regulated by SHR and SCR, plays a central role. In phb shr and phb scr mutants, root meristem/growth activity recovers significantly. Interestingly, this recovery does not accompany the resurgence of QC cells. PHB regulates apical root growth in stele cells of the root meristem, located proximal to the QC. Our genome-wide investigation suggests that PHB exerts its influence on root growth by regulating auxin-cytokinin homeostasis. Apical root growth was restored when cytokinin levels were genetically reduced in the shr mutant. Conversely, when miRNA-resistant PHB was expressed in the root stele cells, apical root growth and meristem functions were significantly inhibited without blocking the QC identity. Taken together, our investigation reveals two mechanisms through which SHR regulates root growth and stem cell activities: one is to specify and maintain the QC and the other is to regulate the proximal meristem activity through PHB and cytokinin.  In this regulation, QC seems to be more involved in maintaining the “growth signal” and thus ensure the indeterminate root growth.

overall_design: Total 7 samples (2 replicates of shr-2 mutant (high PHABULOSA expression) vs. 2 replicates of shr-2 phb-6 (low/absent PHABULOSA expression). 3 replicates of Wild type used as reference sample.

first: Jose

last: Sebastian

first: Jing

last: Zhou


title: Transcription Factor CHF1/Hey2 Regulates Specific Gene Sets in Serum Stimulated Primary Cardiac Myocytes

status: Public on Jan 04 2010

city: Seattle

first: James

middle: William

last: MacDonald

state: WA

address: 4225 Roosevelt Way NE

department: Environmental and Occupational Health Sciences

institute: University of Washington

summary: Background: We have previously found that overexpression of CHF1/Hey2 in the myocardium prevents the development of phenylephrine-induced hypertrophy and promotes physiological hypertrophy in an aortic banding model. To identify transcriptional pathways regulated by CHF1/Hey2 in hypertrophy, we cultured primary neonatal mouse cardiac myocytes from wild type and transgenic mice overexpressing CHF1/Hey2 and treated them with serum, a potent hypertrophic stimulus. We determined transcriptional profiles by hybridization to Affymetrix GeneChip® Mouse Gene 1.0 ST Arrays. We identified important biological processes regulated by CHF1/Hey2 by Gene Set Analysis using Biological Process Gene Sets from the Gene Ontology Consortium. Results: We found that overexpression of CHF1/Hey2 suppresses gene sets involved in water transport, regulation of adenylate cyclase activity, embryonic eye morphogenesis, gut development and fluid transport after serum stimulation. Genes involved in protein dephosphorylation, in contrast, demonstrate increased expression in myocytes overexpressing CHF1/Hey2, and this increase is independent of serum treatment. Genes overexpressed prior to serum treatment are involved in regulation of transcription factor activity, protein export from the nucleus, and steroid hormone receptor signaling. Genes overexpressed after serum treatment are involved in autophagy, apoptosis and mitochondrial biogenesis. Conclusions: CHF1/Hey2 suppresses fluid transport, activation of adenylate cyclase activity, promotes phosphatase activity, autophagy and regulates other important biological processes likely relevant to hypertrophy.

overall_design: Transgenic Mice and Neonatal Mouse Myocyte Culture: WT no serum, 5; WT with serum, 7; TG no serum, 6; TG with serum, 7.

last: Beyer

first: Man

last: Yu

first: Federico

last: Farin

first: Theodor

last: Bammler

last: Chin


title: Abnormal Developmental Control of Replication Timing Domains in Pediatric Acute Lymphoblastic Leukemia

status: Public on May 16 2012

city: Tallahassee

first: Tyrone

last: Ryba

state: FL

address: 319 Stadium Dr.

department: Biological Science

institute: Florida State University

summary: Abnormal replication timing has been observed in cancer but no study has comprehensively evaluated this misregulation. We generated genome-wide replication timing profiles for pediatric leukemias from 17 patients and 3 cell lines, as well as normal B and T cells. Non-leukemic EBV-transformed lymphoblastoid cell lines displayed highly stable replication timing profiles that were more similar to normal T cells than to leukemias. Leukemias were more similar to each other than to B and T cells but were considerably more heterogeneous than non-leukemic controls. Some differences were patient-specific while others were found in all leukemic samples, potentially representing early epigenetic events. Differences encompassed large segments of chromosomes and included genes implicated in other types of cancer. Remarkably, differences that distinguished leukemias aligned in register to the boundaries of developmentally regulated replication timing domains that distinguish normal cell types. Most changes did not coincide with copy number variation or translocations. However, many of the changes that were associated with translocations in some leukemias were also shared between all leukemic samples independent of the genetic lesion, suggesting that they precede and possibly predispose chromosomes to the translocation. Altogether, our results identify sites of abnormal developmental control of DNA replication in cancer that reveal the significance of replication timing boundaries to chromosome structure and function and support the replication domain model of replication timing regulation. They also open new avenues of investigation into the chromosomal basis of cancer and provide a potential novel source of epigenetic cancer biomarkers.

overall_design: Four karyotypically normal B-lymphoblastoid cell types with two replicates each, one peripheral T-lymphoblast replicate, 3 leukemic cell lines with 1-3 replicates each, 17 patient samples with 1-3 replicates each (total of 40 individual replicates)

first: Dana

last: Battaglia


title: Vastus lateralis muscle of patients with an acute COPD exacerbation

status: Public on Mar 14 2009

city: Leuven

first: Tim

last: Crul

address: Herestraat 49 - 706

department: Pathophysiology

country: Belgium

institute: University of Leuven

summary:
To further unravel the potential molecular mechanisms involved in the loss of muscle function during an acute exacerbation, a cross-sectional microarray study was designed to compare the gene expression profile of the vastus lateralis muscle in patients with an acute COPD exacerbation and in stable COPD patients.
Keywords: cross-sectional patient study

overall_design: A cross-sectional microarray study was designed. The microarray screening was performed on a vastus lateralis biopsy obtained from 4 patients with an acute COPD exacerbation and 5 stable COPD patients. No replicates or dye-swaps were included.

first: Dries

last: Testelmans

first: Martijn

last: Spruit

first: Ghislaine

last: Gayan-Ramirez

first: Thierry

last: Troosters

first: Rik

last: Gosselink

first: Ineke

last: Geeraerts

first: Marc

last: Decramer


title: Gene expression profiling of lung tissues from patients with combined pulmonary fibrosis and emphysema

status: Public on Jun 27 2012

city: Matsumoto

first: Masayuki

last: Hanaoka

state: Nagano

address: Asahi 3-1-1

department: First Department of Medicine

country: Japan

institute: Shinshu University School of Medicine

summary:
Combined pulmonary fibrosis and emphysema (CPFE) is characterized by upper-lobe emphysema combined with lower-lobe fibrosis and a high prevalence of pulmonary hypertension. The aim of this study was to measure and analyze gene expression profiles in the lungs of CPFE patients.
The results showed that the expression profiles of the fibrotic and emphysematous lesions were remarkably different in terms of function. Genes related to immune system, structural constituents of cytoskeleton, and cellular adhesion were overexpressed in fibrotic lesions, while genes associated with cellular fraction, cell membrane structures, vascular growth and biology, second-messenger-mediated signaling, and lung development (all processes that contribute to the destruction and repair of cells, vessels, and lung) were overexpressed in emphysematous lesions.
The differences in gene expression were detected in fibrotic and emphysematous lesions in CPFE patients. We propose that the development of coexisted fibrotic and emphysematous lesions in CPFE is implemented by these different patterns of gene expressions.

overall_design: Lung tissue specimens from fibrous lesions and emphysematous lesions of 3 patients with combined pulmonary fibrosis and emphysema (CPFE) were obtained for RNA extraction and hybridization on Affymetrix microarrays. We hypothesized that coexisted fibrosis and emphysema in CPFE are programmed by differential gene expressions in the corresponding lesions in the lungs of smokers susceptible to CPFE. Given the importance of genetic susceptibility in understanding the etiology and pathogenesis of CPFE, we examined tissues from patients with CPFE to systemically identify genes significantly expressed in lung tissues with fibrotic lesions as well as genes significantly expressed in tissues with emphysematous lesions.

first: Michiko

last: Ito

first: Yunden

last: Droma


title: Thrombospondin-1: A Pro-Atherosclerotic Protein Augmented by Hyperglycemia

status: Public on Aug 11 2009

city: Syracuse

first: Frank

last: Middleton

address: 505 Irving Avenue

department: Neuroscience and Physiology

institute: SUNY Upstate Medical Univ

summary: Diabetes is associated with a more aggressive form of atherosclerosis. Thrombospondin-1 (TSP-1), an extracellular matrix protein, is an acute phase reactant that induces vascular smooth muscle (VSMC) migration and proliferation in areas of vascular injury, and is also upregulated in VSMCs exposed to hyperglycemia. We hypothesized that hyperglycemia amplifies the expression of genes induced by TSP-1 in VSMCs. Human aortic VSMCs were cultured in DMEM supplemented with 10 % FBS and 1% antibiotics, cells were used between passages three and five. VSMCs were preincubated in DMEM containing 0.2% FBS with 5 mM glucose (normoglycemia), 25 mM glucose (hyperglycemia), 25 mM mannose (osmotic control), TSP-1 (20µg/mL), 25 mM glucose + TSP-1 (20µg/mL) or 25 mM mannose + TSP-1 (20µg/mL). Data analysis revealed that TSP-1 stimulates gene expression relevant to the pathogenesis of atherosclerosis and diabetic vascular disease.

overall_design: Total RNA was extracted from replicate cultures of human aortic VSMCs and microarray analysis performed for a total of 18 samples (3 replicates per condition) using the Human Gene Array ST.

first: Kristopher

last: Maier

first: Xuan

last: Han

first: Benjamin

last: Sadowitz

first: Karen

middle: L

last: Gentile

first: Vivian

last: Gahtan


title: Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation

status: Public on Dec 03 2010

city: Miami

first: Maria

middle: Eugenia

last: Figueroa

address: 1501 NW 10th Ave, BRB 709A, Locator code C227

department: Human Genetics

institute: University of Miiami

type: Methylation profiling by genome tiling array

summary: Cancer-associated IDH mutations are characterized by neomorphic enzyme activity and resultant 2 hydroxyglutarate (2HG) production. Mutational and epigenetic profiling of a large AML patient cohort revealed that IDH1/2-mutant AMLs display global DNA hypermethylation and a specific hypermethylation signature. Furthermore, expression of 2HG-producing IDH alleles in cells rapidly induced global DNA hypermethylation. In the AML cohort, IDH1/2 mutations were mutually exclusive with mutations in the α-ketoglutarate-dependent enzyme TET2, and TET2 loss-of function mutations associated with similar epigenetic defects as IDH1/2 mutants. Consistent with these genetic and epigenetic data, expression of IDH mutants impaired TET2 catalytic function in cells. Finally, either expression of mutant IDH1/2 or Tet2 depletion impaired hematopoietic differentiation and increased stem cell marker expression, suggesting a shared pro-leukemogenic effect.

overall_design: DNA methylation and gene expression profiling in IDH1/2 mutant vs. IDH1/2 wild-type AML

first: Ari

last: Melnick