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Article ; Online: The ViReflow pipeline enables user friendly large scale viral consensus genome reconstruction.

Moshiri, Niema / Fisch, Kathleen M / Birmingham, Amanda / DeHoff, Peter / Yeo, Gene W / Jepsen, Kristen / Laurent, Louise C / Knight, Rob

Scientific reports

2022 Volume 12, Issue 1, Page(s) 5077

Abstract: Throughout the COVID-19 pandemic, massive sequencing and data sharing efforts enabled the real-time surveillance of novel SARS-CoV-2 strains throughout the world, the results of which provided public health officials with actionable information to ... ...

Abstract	Throughout the COVID-19 pandemic, massive sequencing and data sharing efforts enabled the real-time surveillance of novel SARS-CoV-2 strains throughout the world, the results of which provided public health officials with actionable information to prevent the spread of the virus. However, with great sequencing comes great computation, and while cloud computing platforms bring high-performance computing directly into the hands of all who seek it, optimal design and configuration of a cloud compute cluster requires significant system administration expertise. We developed ViReflow, a user-friendly viral consensus sequence reconstruction pipeline enabling rapid analysis of viral sequence datasets leveraging Amazon Web Services (AWS) cloud compute resources and the Reflow system. ViReflow was developed specifically in response to the COVID-19 pandemic, but it is general to any viral pathogen. Importantly, when utilized with sufficient compute resources, ViReflow can trim, map, call variants, and call consensus sequences from amplicon sequence data from 1000 SARS-CoV-2 samples at 1000X depth in < 10 min, with no user intervention. ViReflow's simplicity, flexibility, and scalability make it an ideal tool for viral molecular epidemiological efforts.
MeSH term(s)	COVID-19/epidemiology ; Genome, Viral/genetics ; Humans ; Pandemics ; SARS-CoV-2/genetics ; Software
Language	English
Publishing date	2022-03-24
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-022-09035-w
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: An iPSC line derived from a human acute myeloid leukemia cell line (HL-60-iPSC) retains leukemic abnormalities and displays myeloid differentiation defects.

Yamasaki, Amanda E / Warshaw, Jane N / Kyalwazi, Beverly L / Matsui, Hiroko / Jepsen, Kristen / Panopoulos, Athanasia D

Stem cell research

2020 Volume 49, Page(s) 102096

Abstract: Cancer-derived iPSCs have provided valuable insight into oncogenesis, but human cancer cells can often be difficult to reprogram, especially in cases of complex genetic abnormalities. Here we report, to our knowledge, the first successful generation of ... ...

Abstract	Cancer-derived iPSCs have provided valuable insight into oncogenesis, but human cancer cells can often be difficult to reprogram, especially in cases of complex genetic abnormalities. Here we report, to our knowledge, the first successful generation of an iPSC line from a human immortalized acute myeloid leukemia (AML) cell line, the cell line HL-60. This iPSC line retains a majority of the leukemic genotype and displays defects in myeloid differentiation, thus providing a tool for modeling and studying AML.
MeSH term(s)	Cell Differentiation ; HL-60 Cells ; Hematopoiesis ; Humans ; Induced Pluripotent Stem Cells ; Leukemia, Myeloid, Acute/genetics
Language	English
Publishing date	2020-11-23
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	1876-7753
ISSN (online)	1876-7753
DOI	10.1016/j.scr.2020.102096
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Article ; Online: The unfolded protein response links tumor aneuploidy to local immune dysregulation.

Xian, Su / Dosset, Magalie / Almanza, Gonzalo / Searles, Stephen / Sahani, Paras / Waller, T Cameron / Jepsen, Kristen / Carter, Hannah / Zanetti, Maurizio

EMBO reports

2021 Volume 22, Issue 12, Page(s) e52509

Abstract: Aneuploidy is a chromosomal abnormality associated with poor prognosis in many cancer types. Here, we tested the hypothesis that the unfolded protein response (UPR) mechanistically links aneuploidy and local immune dysregulation. Using a single somatic ... ...

Abstract	Aneuploidy is a chromosomal abnormality associated with poor prognosis in many cancer types. Here, we tested the hypothesis that the unfolded protein response (UPR) mechanistically links aneuploidy and local immune dysregulation. Using a single somatic copy number alteration (SCNA) score inclusive of whole-chromosome, chromosome arm, and focal alterations in a pan-cancer analysis of 9,375 samples in The Cancer Genome Atlas (TCGA) database, we found an inverse correlation with a cytotoxicity (CYT) score across disease stages. Co-expression patterns of UPR genes changed substantially between SCNA
MeSH term(s)	Aneuploidy ; Humans ; Neoplasms/genetics ; Tumor Microenvironment ; Unfolded Protein Response
Language	English
Publishing date	2021-10-26
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2020896-0
ISSN	1469-3178 ; 1469-221X
ISSN (online)	1469-3178
ISSN	1469-221X
DOI	10.15252/embr.202152509
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Article ; Online: The ViReflow pipeline enables user friendly large scale viral consensus genome reconstruction

Niema Moshiri / Kathleen M. Fisch / Amanda Birmingham / Peter DeHoff / Gene W. Yeo / Kristen Jepsen / Louise C. Laurent / Rob Knight

Scientific Reports, Vol 12, Iss 1, Pp 1-

2022 Volume 6

Abstract: Abstract Throughout the COVID-19 pandemic, massive sequencing and data sharing efforts enabled the real-time surveillance of novel SARS-CoV-2 strains throughout the world, the results of which provided public health officials with actionable information ... ...

Abstract	Abstract Throughout the COVID-19 pandemic, massive sequencing and data sharing efforts enabled the real-time surveillance of novel SARS-CoV-2 strains throughout the world, the results of which provided public health officials with actionable information to prevent the spread of the virus. However, with great sequencing comes great computation, and while cloud computing platforms bring high-performance computing directly into the hands of all who seek it, optimal design and configuration of a cloud compute cluster requires significant system administration expertise. We developed ViReflow, a user-friendly viral consensus sequence reconstruction pipeline enabling rapid analysis of viral sequence datasets leveraging Amazon Web Services (AWS) cloud compute resources and the Reflow system. ViReflow was developed specifically in response to the COVID-19 pandemic, but it is general to any viral pathogen. Importantly, when utilized with sufficient compute resources, ViReflow can trim, map, call variants, and call consensus sequences from amplicon sequence data from 1000 SARS-CoV-2 samples at 1000X depth in < 10 min, with no user intervention. ViReflow’s simplicity, flexibility, and scalability make it an ideal tool for viral molecular epidemiological efforts.
Keywords	Medicine ; R ; Science ; Q
Language	English
Publishing date	2022-03-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Two iPSC lines generated from the bone marrow of a relapsed/refractory AML patient display normal karyotypes and myeloid differentiation potential.

Yamasaki, Amanda E / King, Nicholas E / Matsui, Hiroko / Jepsen, Kristen / Panopoulos, Athanasia D

Stem cell research

2019 Volume 41, Page(s) 101587

Abstract: Using iPSCs to study cancer has been complicated by the fact that many cancer cells are difficult to reprogram, which has been attributed to the genomic abnormalities present. Acute Myeloid Leukemia (AML) is a complex disease that presents with various ... ...

Abstract	Using iPSCs to study cancer has been complicated by the fact that many cancer cells are difficult to reprogram, which has been attributed to the genomic abnormalities present. Acute Myeloid Leukemia (AML) is a complex disease that presents with various types of genomic aberrations that affect prognosis. Here we reprogrammed CD34+ cells from an AML patient containing a rare der(7)t(7;13) translocation associated with poor prognosis, who had relapsed and was refractory to current treatments. The generated AML-iPSCs displayed normal karyotypes and myeloid differentiation potential. These findings have implications for modeling and treating AML disease.
MeSH term(s)	Aged ; Bone Marrow/pathology ; Cell Differentiation ; Drug Resistance, Neoplasm ; Humans ; Induced Pluripotent Stem Cells/pathology ; Karyotype ; Leukemia, Myeloid, Acute/pathology ; Male ; Myeloid Cells/pathology ; Neoplasm Recurrence, Local/pathology ; Tumor Cells, Cultured
Language	English
Publishing date	2019-10-17
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	1876-7753
ISSN (online)	1876-7753
DOI	10.1016/j.scr.2019.101587
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Article ; Online: Nuclear corepressors NCOR1/NCOR2 regulate B cell development, maintain genomic integrity and prevent transformation.

Lee, Robin D / Knutson, Todd P / Munro, Sarah A / Miller, Jeffrey T / Heltemes-Harris, Lynn M / Mullighan, Charles G / Jepsen, Kristen / Farrar, Michael A

Nature immunology

2022 Volume 23, Issue 12, Page(s) 1763–1776

Abstract: The nuclear corepressors NCOR1 and NCOR2 interact with transcription factors involved in B cell development and potentially link these factors to alterations in chromatin structure and gene expression. Herein, we demonstrate that Ncor1/2 deletion limits ... ...

Abstract	The nuclear corepressors NCOR1 and NCOR2 interact with transcription factors involved in B cell development and potentially link these factors to alterations in chromatin structure and gene expression. Herein, we demonstrate that Ncor1/2 deletion limits B cell differentiation via impaired recombination, attenuates pre-BCR signaling and enhances STAT5-dependent transcription. Furthermore, NCOR1/2-deficient B cells exhibited derepression of EZH2-repressed gene modules, including the p53 pathway. These alterations resulted in aberrant Rag1 and Rag2 expression and accessibility. Whole-genome sequencing of Ncor1/2 DKO B cells identified increased number of structural variants with cryptic recombination signal sequences. Finally, deletion of Ncor1 alleles in mice facilitated leukemic transformation, whereas human leukemias with less NCOR1 correlated with worse survival. NCOR1/2 mutations in human leukemia correlated with increased RAG expression and number of structural variants. These studies illuminate how the corepressors NCOR1/2 regulate B cell differentiation and provide insights into how NCOR1/2 mutations may promote B cell transformation.
MeSH term(s)	Mice ; Humans ; Animals ; Co-Repressor Proteins ; Hematopoiesis ; Signal Transduction ; Cell Nucleus ; Genomics ; Nuclear Receptor Co-Repressor 2/genetics ; Nuclear Receptor Co-Repressor 1/genetics
Chemical Substances	Co-Repressor Proteins ; NCOR2 protein, human ; Nuclear Receptor Co-Repressor 2 ; NCOR1 protein, human ; Nuclear Receptor Co-Repressor 1 ; Ncor1 protein, mouse
Language	English
Publishing date	2022-10-31
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2016987-5
ISSN	1529-2916 ; 1529-2908
ISSN (online)	1529-2916
ISSN	1529-2908
DOI	10.1038/s41590-022-01343-7
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Article ; Online: Two iPSC lines generated from the bone marrow of a relapsed/refractory AML patient display normal karyotypes and myeloid differentiation potential

Amanda E. Yamasaki / Nicholas E. King / Hiroko Matsui / Kristen Jepsen / Athanasia D. Panopoulos

Stem Cell Research, Vol 41, Iss , Pp - (2019)

2019

Abstract	Using iPSCs to study cancer has been complicated by the fact that many cancer cells are difficult to reprogram, which has been attributed to the genomic abnormalities present. Acute Myeloid Leukemia (AML) is a complex disease that presents with various types of genomic aberrations that affect prognosis. Here we reprogrammed CD34+ cells from an AML patient containing a rare der(7)t(7;13) translocation associated with poor prognosis, who had relapsed and was refractory to current treatments. The generated AML-iPSCs displayed normal karyotypes and myeloid differentiation potential. These findings have implications for modeling and treating AML disease. Keywords: Acute Myeloid Leukemia, Bone marrow cells, Disease modeling, Reprogramming, Induced pluripotent stem cells
Keywords	Biology (General) ; QH301-705.5
Language	English
Publishing date	2019-12-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: An iPSC line derived from a human acute myeloid leukemia cell line (HL-60-iPSC) retains leukemic abnormalities and displays myeloid differentiation defects

Amanda E. Yamasaki / Jane N. Warshaw / Beverly L. Kyalwazi / Hiroko Matsui / Kristen Jepsen / Athanasia D. Panopoulos

Stem Cell Research, Vol 49, Iss , Pp 102096- (2020)

2020

Abstract	Cancer-derived iPSCs have provided valuable insight into oncogenesis, but human cancer cells can often be difficult to reprogram, especially in cases of complex genetic abnormalities. Here we report, to our knowledge, the first successful generation of an iPSC line from a human immortalized acute myeloid leukemia (AML) cell line, the cell line HL-60. This iPSC line retains a majority of the leukemic genotype and displays defects in myeloid differentiation, thus providing a tool for modeling and studying AML.
Keywords	Biology (General) ; QH301-705.5
Language	English
Publishing date	2020-12-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Extracellular vesicles produced in B cells deliver tumor suppressor miR-335 to breast cancer cells disrupting oncogenic programming in vitro and in vivo.

Almanza, Gonzalo / Rodvold, Jeffrey J / Tsui, Brian / Jepsen, Kristen / Carter, Hannah / Zanetti, Maurizio

Scientific reports

2018 Volume 8, Issue 1, Page(s) 17581

Abstract: The successful implementation of miRNA (miR) therapies in humans will ultimately rely on the use of vehicles with improved cellular delivery capability. Here we tested a new system that leverages extracellular vesicles (EVs) laden with a tumor suppressor ...

Abstract	The successful implementation of miRNA (miR) therapies in humans will ultimately rely on the use of vehicles with improved cellular delivery capability. Here we tested a new system that leverages extracellular vesicles (EVs) laden with a tumor suppressor miRNA (miR-335) produced in B cells by plasmid DNA induction (iEVs). We demonstrate that iEVs-335 efficiently and durably restored the endogenous miR-335 pool in human triple negative breast cancer cells, downregulated the expression of the miR-335 target gene SOX4 transcription factor, and markedly inhibited tumor growth in vivo. Remarkably, iEVs-335 mediated transcriptional effects that persisted in tumors after 60 days post orthotopic implantation. Genome-wide RNASeq analysis of cancer cells treated in vitro with iEVs-335 showed the regulation of a discrete number of genes only, without broad transcriptome perturbations. This new technology may be ideally suited for therapies aimed to restore tumor suppressor miRNAs in cancer cells, disrupting the oncogenic program established after escape from miRNA control.
MeSH term(s)	Animals ; B-Lymphocytes/metabolism ; Carcinogenesis/drug effects ; Cell Line, Tumor ; Extracellular Vesicles/metabolism ; Gene Expression Regulation, Neoplastic ; Genes, Tumor Suppressor ; Humans ; Mice ; Mice, Inbred NOD ; MicroRNAs/genetics ; SOXC Transcription Factors/metabolism ; Signal Transduction/drug effects ; Triple Negative Breast Neoplasms/genetics ; Triple Negative Breast Neoplasms/therapy ; Xenograft Model Antitumor Assays
Chemical Substances	MIRN335 microRNA, human ; MicroRNAs ; SOX4 protein, human ; SOXC Transcription Factors
Language	English
Publishing date	2018-12-04
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-018-35968-2
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: The breast pre-cancer atlas illustrates the molecular and micro-environmental diversity of ductal carcinoma in situ.

Nachmanson, Daniela / Officer, Adam / Mori, Hidetoshi / Gordon, Jonathan / Evans, Mark F / Steward, Joseph / Yao, Huazhen / O'Keefe, Thomas / Hasteh, Farnaz / Stein, Gary S / Jepsen, Kristen / Weaver, Donald L / Hirst, Gillian L / Sprague, Brian L / Esserman, Laura J / Borowsky, Alexander D / Stein, Janet L / Harismendy, Olivier

NPJ breast cancer

2022 Volume 8, Issue 1, Page(s) 6

Abstract: Microenvironmental and molecular factors mediating the progression of Breast Ductal Carcinoma In Situ (DCIS) are not well understood, impeding the development of prevention strategies and the safe testing of treatment de-escalation. We addressed ... ...

Abstract	Microenvironmental and molecular factors mediating the progression of Breast Ductal Carcinoma In Situ (DCIS) are not well understood, impeding the development of prevention strategies and the safe testing of treatment de-escalation. We addressed methodological barriers and characterized the mutational, transcriptional, histological, and microenvironmental landscape across 85 multiple microdissected regions from 39 cases. Most somatic alterations, including whole-genome duplications, were clonal, but genetic divergence increased with physical distance. Phenotypic and subtype heterogeneity was frequently associated with underlying genetic heterogeneity and regions with low-risk features preceded those with high-risk features according to the inferred phylogeny. B- and T-lymphocytes spatial analysis identified three immune states, including an epithelial excluded state located preferentially at DCIS regions, and characterized by histological and molecular features of immune escape, independently from molecular subtypes. Such breast pre-cancer atlas with uniquely integrated observations will help scope future expansion studies and build finer models of outcomes and progression risk.
Language	English
Publishing date	2022-01-13
Publishing country	United States
Document type	Journal Article
ISSN	2374-4677
ISSN	2374-4677
DOI	10.1038/s41523-021-00365-y
Database	MEDical Literature Analysis and Retrieval System OnLINE

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