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Article ; Online: Novel biosensor for high-throughput detection of progesterone receptor-interacting endocrine disruptors.

Stavreva, Diana A / Varticovski, Lyuba / Raziuddin, Razi / Pegoraro, Gianluca / Schiltz, R Louis / Hager, Gordon L

2024 Volume 14, Issue 1, Page(s) 5567

Abstract: Progesterone receptor (PR)-interacting compounds in the environment are associated with serious health hazards. However, methods for their detection in environmental samples are cumbersome. We report a sensitive activity-based biosensor for rapid and ... ...

Abstract	Progesterone receptor (PR)-interacting compounds in the environment are associated with serious health hazards. However, methods for their detection in environmental samples are cumbersome. We report a sensitive activity-based biosensor for rapid and reliable screening of progesterone receptor (PR)-interacting endocrine disrupting chemicals (EDCs). The biosensor is a cell line which expresses nuclear mCherry-NF1 and a green fluorescent protein (GFP)-tagged chimera of glucocorticoid receptor (GR) N terminus fused to the ligand binding domain (LBD) of PR (GFP-GR-PR). As this LBD is shared by the PRA and PRB, the biosensor reports on the activation of both PR isoforms. This GFP-GR-PR chimera is cytoplasmic in the absence of hormone and translocates rapidly to the nucleus in response to PR agonists or antagonists in concentration- and time-dependent manner. In live cells, presence of nuclear NF1 label eliminates cell fixation and nuclear staining resulting in efficient screening. The assay can be used in screens for novel PR ligands and PR-interacting contaminants in environmental samples. A limited screen of river water samples indicated a widespread, low-level contamination with PR-interacting contaminants in all tested samples.
MeSH term(s)	Endocrine Disruptors ; Receptors, Progesterone/genetics ; Biological Assay ; Cell Line ; Cytoplasm ; Green Fluorescent Proteins/genetics ; Receptors, Glucocorticoid/genetics
Chemical Substances	Endocrine Disruptors ; Receptors, Progesterone ; Green Fluorescent Proteins (147336-22-9) ; Receptors, Glucocorticoid
Language	English
Publishing date	2024-03-06
Publishing country	England
Document type	Journal Article
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-024-55254-8
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Author Correction: A purine scaffold Hsp90 inhibitor destabilizes BCL-6 and has specific antitumor activity in BCL-6-dependent B cell lymphomas.

Cerchietti, Leandro C / Lopes, Eloisi C / Yang, Shao Ning / Hatzi, Katerina / Bunting, Karen L / Tsikitas, Lucas A / Mallik, Alka / Robles, Ana I / Walling, Jennifer / Varticovski, Lyuba / Shaknovich, Rita / Bhalla, Kapil N / Chiosis, Gabriela / Melnick, Ari

Nature medicine

2024

Language	English
Publishing date	2024-04-03
Publishing country	United States
Document type	Published Erratum
ZDB-ID	1220066-9
ISSN	1546-170X ; 1078-8956
ISSN (online)	1546-170X
ISSN	1078-8956
DOI	10.1038/s41591-024-02957-0
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Zs.A 4212: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Book: Demystifying medicine 2015

Varticovski, Lyuba / Apolo, Andrea

chromosomes and a major disease

2015

Title variant	Bladder cancer
Institution	National Institutes of Health (U.S.),
Author's details	Lyuba Varticovski, Andrea Apolo
MeSH term(s)	Urinary Bladder Neoplasms/therapy ; Urinary Bladder Neoplasms/genetics
Language	English
Size	1 online resource (1 streaming video file (1 hr., 48 min.)) :, color, sound
Document type	Book
Note	Closed-captioned.
Database	Catalogue of the US National Library of Medicine (NLM)

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Article ; Online: Genome-wide Analysis Identifies Nuclear Factor 1C as a Novel Transcription Factor and Potential Therapeutic Target in Small Cell Lung Cancer.

Shukla, Vivek / Wang, Haitao / Varticovski, Lyuba / Baek, Songjoon / Wang, Ruihong / Wu, Xinwei / Echtenkamp, Frank / Hernandez, Frank Villa / Prothro, Katherine P / Gara, Sudheer K / Zhang, Mary R / Shiffka, Stephanie / Raziuddin, Razi / Neckers, Leonard M / Linehan, W Marston / Chen, Haobin / Hager, Gordon L / Schrump, David S

Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer

2024

Abstract: Background: Recent insights regarding mechanisms mediating stemness, heterogeneity, and metastatic potential of lung cancers have yet to be fully translated to effective regimens for the treatment of these malignancies. This study sought to identify ... ...

Abstract	Background: Recent insights regarding mechanisms mediating stemness, heterogeneity, and metastatic potential of lung cancers have yet to be fully translated to effective regimens for the treatment of these malignancies. This study sought to identify novel targets for lung cancer therapy. Methods: Transcriptomes and DNA methylomes of 14 SCLC and 10 NSCLC lines were compared to normal human small airway epithelial cells (SAEC) and induced pluripotent stem cell (iPSC) clones derived from SAEC. SCLC lines, lung iPSC (Lu-iPSC), and SAEC were further evaluated by DNase I hypersensitivity (DHS-seq). Changes in chromatin accessibility and depths of transcription factor (TF) footprints were quantified using Bivariate analysis of Genomic Footprint. Standard techniques were used to examine growth and tumorigenencity as well as changes in transcriptomes and glucose metabolism of SCLC cells following Nuclear Factor 1C (NFIC) knockdown, and to examine NFIC expression in SCLC cells following exposure to BET inhibitors. Results: Significant commonality of transcriptomes and DNA methylomes was observed between Lu-iPSC and SCLC; however, this analysis was uninformative regarding pathways unique to lung cancer. Linking results of DNase-seq to RNA-seq enabled identification of networks not previously associated with SCLC. When combined with footprint depth, NFIC, a transcription factor not previously associated with SCLC, had the highest score of occupancy at open chromatin sites. Knockdown of NFIC impaired glucose metabolism, decreased stemness, and inhibited growth of SCLC cells in-vitro and in-vivo. ChIP-seq analysis identified numerous sites occupied by Bromodomain-containing protein 4 (BRD4) in the NFIC promoter region. Knock-down of BRD4 or treatment with Bromodomain and extra-terminal domain (BET) inhibitors (BETi) markedly reduced NFIC expression in SCLC cells and SCLC PDX models. Approximately 8% of genes downregulated by BETi treatment were repressed by NFIC knockdown in SCLC, while 34% of genes repressed following NFIC knockdown were also downregulated in SCLC cells following BETi treatment. Conclusions: NFIC is a key TF and possible mediator of transcriptional regulation by BET family proteins in SCLC. Our findings highlight the potential of genome-wide chromatin accessibility analysis for elucidating mechanisms of pulmonary carcinogenesis and identifying novel targets for lung cancer therapy.
Language	English
Publishing date	2024-04-05
Publishing country	United States
Document type	Journal Article
ZDB-ID	2432037-7
ISSN	1556-1380 ; 1556-0864
ISSN (online)	1556-1380
ISSN	1556-0864
DOI	10.1016/j.jtho.2024.03.023
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Zs.A 6664: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)
Zs.MO 652: Show issues

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Article ; Online: High Quality ATAC-Seq Data Recovered from Cryopreserved Breast Cell Lines and Tissue.

Fujiwara, Saori / Baek, Songjoon / Varticovski, Lyuba / Kim, Sohyoung / Hager, Gordon L

Scientific reports

2019 Volume 9, Issue 1, Page(s) 516

Abstract: DNA accessibility to transcription regulators varies between cells and modulates gene expression patterns. Several "open" chromatin profiling methods that provide valuable insight into the activity of these regulatory regions have been developed. However, ...

Abstract	DNA accessibility to transcription regulators varies between cells and modulates gene expression patterns. Several "open" chromatin profiling methods that provide valuable insight into the activity of these regulatory regions have been developed. However, their application to clinical samples has been limited despite the discovery that the Analysis of Transposase-Accessible Chromatin followed by sequencing (ATAC-seq) method can be performed using fewer cells than other techniques. Obtaining fresh rather than stored samples and a lack of adequate optimization and quality controls are major barriers to ATAC's clinical implementation. Here, we describe an optimized ATAC protocol in which we varied nuclear preparation conditions and transposase concentrations and applied rigorous quality control measures before testing fresh, flash frozen, and cryopreserved breast cells and tissue. We obtained high quality data from small cell number. Furthermore, the genomic distribution of sequencing reads, their enrichment at transcription start sites, and transcription factor footprint analyses were similar between cryopreserved and fresh samples. This updated method is applicable to clinical samples, including cells from fine needle aspiration and tissues obtained via core needle biopsy or surgery. Chromatin accessibility analysis using patient samples will greatly expand the range of translational research and personalized medicine by identification of clinically-relevant epigenetic features.
MeSH term(s)	Animals ; Breast/cytology ; Breast/metabolism ; Breast Neoplasms/genetics ; Cell Nucleus/genetics ; Chromatin/genetics ; Chromatin Immunoprecipitation Sequencing/methods ; Cryopreservation ; DNA/genetics ; Female ; Humans ; MCF-7 Cells ; Mice ; Mice, Inbred C57BL
Chemical Substances	Chromatin ; DNA (9007-49-2)
Language	English
Publishing date	2019-01-24
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Intramural
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-018-36927-7
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Chromatin in time and space.

Hager, Gordon L / Varticovski, Lyuba

Biochimica et biophysica acta

2012 Volume 1819, Issue 7, Page(s) 631

MeSH term(s)	Chromatin/metabolism ; Chromatin/physiology ; Chromatin Assembly and Disassembly ; Government Programs ; Humans ; National Institutes of Health (U.S.) ; United States
Chemical Substances	Chromatin
Language	English
Publishing date	2012-05-17
Publishing country	Netherlands
Document type	Editorial
ZDB-ID	60-7
ISSN	1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650 ; 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
ISSN (online)	1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650
ISSN	0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
DOI	10.1016/j.bbagrm.2012.05.002
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Article ; Online: Genome-Wide Chromatin Landscape Transitions Identify Novel Pathways in Early Commitment to Osteoblast Differentiation.

Thompson, Bethtrice / Varticovski, Lyuba / Baek, Songjoon / Hager, Gordon L

PloS one

2016 Volume 11, Issue 2, Page(s) e0148619

Abstract: Bone continuously undergoes remodeling by a tightly regulated process that involves osteoblast differentiation from Mesenchymal Stem Cells (MSC). However, commitment of MSC to osteoblastic lineage is a poorly understood process. Chromatin organization ... ...

Abstract	Bone continuously undergoes remodeling by a tightly regulated process that involves osteoblast differentiation from Mesenchymal Stem Cells (MSC). However, commitment of MSC to osteoblastic lineage is a poorly understood process. Chromatin organization functions as a molecular gatekeeper of DNA functions. Detection of sites that are hypersensitive to Dnase I has been used for detailed examination of changes in response to hormones and differentiation cues. To investigate the early steps in commitment of MSC to osteoblasts, we used a model human temperature-sensitive cell line, hFOB. When shifted to non-permissive temperature, these cells undergo "spontaneous" differentiation that takes several weeks, a process that is greatly accelerated by osteogenic induction media. We performed Dnase I hypersensitivity assays combined with deep sequencing to identify genome-wide potential regulatory events in cells undergoing early steps of commitment to osteoblasts. Massive reorganization of chromatin occurred within hours of differentiation. Whereas ~30% of unique DHS sites were located in the promoters, the majority was outside of the promoters, designated as enhancers. Many of them were at novel genomic sites and need to be confirmed experimentally. We developed a novel method for identification of cellular networks based solely on DHS enhancers signature correlated to gene expression. The analysis of enhancers that were unique to differentiating cells led to identification of bone developmental program encompassing 147 genes that directly or indirectly participate in osteogenesis. Identification of these pathways provided an unprecedented view of genomic regulation during early steps of differentiation and changes related to WNT, AP-1 and other pathways may have therapeutic implications.
MeSH term(s)	Adipogenesis/genetics ; Binding Sites ; Cell Cycle/genetics ; Cell Differentiation/genetics ; Cell Line ; Chromatin/genetics ; Chromatin/metabolism ; Chromatin Immunoprecipitation ; Cluster Analysis ; Computational Biology/methods ; Gene Expression Profiling ; Gene Expression Regulation ; Genome-Wide Association Study/methods ; High-Throughput Nucleotide Sequencing ; Humans ; Molecular Sequence Annotation ; Nucleotide Motifs ; Osteoblasts/cytology ; Osteoblasts/metabolism ; Osteogenesis/physiology ; Protein Binding ; Regulatory Sequences, Ribonucleic Acid ; Signal Transduction ; Transcription Factors/metabolism ; Transcriptome
Chemical Substances	Chromatin ; Regulatory Sequences, Ribonucleic Acid ; Transcription Factors
Language	English
Publishing date	2016-02-18
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Intramural
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0148619
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Mapping multiple endocrine disrupting activities in Virginia rivers using effect-based assays

Stavreva, Diana A. / Collins, Michael / McGowan, Andrew / Varticovski, Lyuba / Raẓī, Raẓīuddīn / Brody, David Owen / Zhao, Jerry / Lee, Johnna / Kuehn, Riley / Dehareng, Elisabeth / Mazza, Nicholas / Pegoraro, Gianluca / Hager, Gordon L.

Science of the total environment. 2021 June 15, v. 773 p.145602-

2021

Abstract: Water sources are frequently contaminated with natural and anthropogenic substances having known or suspected endocrine disrupting activities; however, these activities are not routinely measured and monitored. Phenotypic bioassays are a promising new ... ...

Abstract	Water sources are frequently contaminated with natural and anthropogenic substances having known or suspected endocrine disrupting activities; however, these activities are not routinely measured and monitored. Phenotypic bioassays are a promising new approach for detection and quantitation of endocrine disrupting chemicals (EDCs). We developed cell lines expressing fluorescent chimeric constructs capable of detecting environmental contaminants which interact with multiple nuclear receptors. Using these assays, we tested water samples collected in the summers of 2016, 2017 and 2018 from two major Virginia rivers. Samples were concentrated 200× and screened for contaminants interacting with the androgen (AR), glucocorticoid (GR), aryl hydrocarbon (AhR) and thyroid receptors. Among 45 tested sites, over 70% had AR activity and 60% had AhR activity. Many sites were also positive for GR and TRβ activation (22% and 42%, respectively). Multiple sites were positive for more than one type of contaminants, indicating presence of complex mixtures. These activities may negatively impact river ecosystems and consequently human health.
Keywords	androgens ; environment ; fluorescence ; glucocorticoids ; human health ; phenotype ; pollution ; rivers ; Virginia ; AR ; GR ; AhR ; TR ; Dex ; Testo ; T3 ; CAY ; DMSO ; Biological activity ; Hormones ; Endocrine disrupting compounds ; River water
Language	English
Dates of publication	2021-0615
Publishing place	Elsevier B.V.
Document type	Article ; Online
ZDB-ID	121506-1
ISSN	1879-1026 ; 0048-9697
ISSN (online)	1879-1026
ISSN	0048-9697
DOI	10.1016/j.scitotenv.2021.145602
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Mapping multiple endocrine disrupting activities in Virginia rivers using effect-based assays.

Stavreva, Diana A / Collins, Michael / McGowan, Andrew / Varticovski, Lyuba / Raziuddin, Razi / Brody, David Owen / Zhao, Jerry / Lee, Johnna / Kuehn, Riley / Dehareng, Elisabeth / Mazza, Nicholas / Pegoraro, Gianluca / Hager, Gordon L

The Science of the total environment

2021 Volume 773, Page(s) 145602

Abstract	Water sources are frequently contaminated with natural and anthropogenic substances having known or suspected endocrine disrupting activities; however, these activities are not routinely measured and monitored. Phenotypic bioassays are a promising new approach for detection and quantitation of endocrine disrupting chemicals (EDCs). We developed cell lines expressing fluorescent chimeric constructs capable of detecting environmental contaminants which interact with multiple nuclear receptors. Using these assays, we tested water samples collected in the summers of 2016, 2017 and 2018 from two major Virginia rivers. Samples were concentrated 200× and screened for contaminants interacting with the androgen (AR), glucocorticoid (GR), aryl hydrocarbon (AhR) and thyroid receptors. Among 45 tested sites, over 70% had AR activity and 60% had AhR activity. Many sites were also positive for GR and TRβ activation (22% and 42%, respectively). Multiple sites were positive for more than one type of contaminants, indicating presence of complex mixtures. These activities may negatively impact river ecosystems and consequently human health.
MeSH term(s)	Biological Assay ; Ecosystem ; Endocrine Disruptors/analysis ; Endocrine Disruptors/toxicity ; Environmental Monitoring ; Humans ; Rivers ; Virginia ; Water Pollutants, Chemical/analysis ; Water Pollutants, Chemical/toxicity
Chemical Substances	Endocrine Disruptors ; Water Pollutants, Chemical
Language	English
Publishing date	2021-02-04
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	121506-1
ISSN	1879-1026 ; 0048-9697
ISSN (online)	1879-1026
ISSN	0048-9697
DOI	10.1016/j.scitotenv.2021.145602
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Zs.A 949: Show issues

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Article: Complex dynamics of transcription regulation

Stavreva, Diana A / Varticovski, Lyuba / Hager, Gordon L

BBA - Gene Regulatory Mechanisms. 2012 July, v. 1819, no. 7

2012

Abstract: Transcription is a tightly regulated cellular function which can be triggered by endogenous (intrinsic) or exogenous (extrinsic) signals. The development of novel techniques to examine the dynamic behavior of transcription factors and the analysis of ... ...

Abstract	Transcription is a tightly regulated cellular function which can be triggered by endogenous (intrinsic) or exogenous (extrinsic) signals. The development of novel techniques to examine the dynamic behavior of transcription factors and the analysis of transcriptional activity at the single cell level with increased temporal resolution has revealed unexpected elements of stochasticity and dynamics of this process. Emerging research reveals a complex picture, wherein a wide range of time scales and temporal transcription patterns overlap to generate transcriptional programs. The challenge now is to develop a perspective that can guide us to common underlying mechanisms, and consolidate these findings. Here we review the recent literature on temporal dynamics and stochastic gene regulation patterns governed by intrinsic or extrinsic signals, utilizing the glucocorticoid receptor (GR)-mediated transcriptional model to illustrate commonality of these emerging concepts. This article is part of a Special Issue entitled: Chromatin in time and space.
Keywords	glucocorticoid receptors ; models ; space and time ; transcription (genetics) ; genes ; chromatin
Language	English
Dates of publication	2012-07
Size	p. 657-666.
Publishing place	Elsevier B.V.
Document type	Article
Note	2019-12-06
ZDB-ID	2918786-2
ISSN	1876-4320 ; 1874-9399
ISSN (online)	1876-4320
ISSN	1874-9399
DOI	10.1016/j.bbagrm.2012.03.004
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