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  1. Article ; Online: Machine learning multi-omics analysis reveals cancer driver dysregulation in pan-cancer cell lines compared to primary tumors.

    Sanders, Lauren M / Chandra, Rahul / Zebarjadi, Navid / Beale, Holly C / Lyle, A Geoffrey / Rodriguez, Analiz / Kephart, Ellen Towle / Pfeil, Jacob / Cheney, Allison / Learned, Katrina / Currie, Rob / Gitlin, Leonid / Vengerov, David / Haussler, David / Salama, Sofie R / Vaske, Olena M

    Communications biology

    2022  Volume 5, Issue 1, Page(s) 1367

    Abstract: Cancer cell lines have been widely used for decades to study biological processes driving cancer development, and to identify biomarkers of response to therapeutic agents. Advances in genomic sequencing have made possible large-scale genomic ... ...

    Abstract Cancer cell lines have been widely used for decades to study biological processes driving cancer development, and to identify biomarkers of response to therapeutic agents. Advances in genomic sequencing have made possible large-scale genomic characterizations of collections of cancer cell lines and primary tumors, such as the Cancer Cell Line Encyclopedia (CCLE) and The Cancer Genome Atlas (TCGA). These studies allow for the first time a comprehensive evaluation of the comparability of cancer cell lines and primary tumors on the genomic and proteomic level. Here we employ bulk mRNA and micro-RNA sequencing data from thousands of samples in CCLE and TCGA, and proteomic data from partner studies in the MD Anderson Cell Line Project (MCLP) and The Cancer Proteome Atlas (TCPA), to characterize the extent to which cancer cell lines recapitulate tumors. We identify dysregulation of a long non-coding RNA and microRNA regulatory network in cancer cell lines, associated with differential expression between cell lines and primary tumors in four key cancer driver pathways: KRAS signaling, NFKB signaling, IL2/STAT5 signaling and TP53 signaling. Our results emphasize the necessity for careful interpretation of cancer cell line experiments, particularly with respect to therapeutic treatments targeting these important cancer pathways.
    MeSH term(s) Humans ; Proteomics ; Multiomics ; Neoplasms/genetics ; Neoplasms/metabolism ; Machine Learning ; Cell Line
    Language English
    Publishing date 2022-12-13
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 2399-3642
    ISSN (online) 2399-3642
    DOI 10.1038/s42003-022-04075-4
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: The case for using mapped exonic non-duplicate reads when reporting RNA-sequencing depth: examples from pediatric cancer datasets.

    Beale, Holly C / Roger, Jacquelyn M / Cattle, Matthew A / McKay, Liam T / Thompson, Drew K A / Learned, Katrina / Lyle, A Geoffrey / Kephart, Ellen T / Currie, Rob / Lam, Du Linh / Sanders, Lauren / Pfeil, Jacob / Vivian, John / Bjork, Isabel / Salama, Sofie R / Haussler, David / Vaske, Olena M

    GigaScience

    2021  Volume 10, Issue 3

    Abstract: Background: The reproducibility of gene expression measured by RNA sequencing (RNA-Seq) is dependent on the sequencing depth. While unmapped or non-exonic reads do not contribute to gene expression quantification, duplicate reads contribute to the ... ...

    Abstract Background: The reproducibility of gene expression measured by RNA sequencing (RNA-Seq) is dependent on the sequencing depth. While unmapped or non-exonic reads do not contribute to gene expression quantification, duplicate reads contribute to the quantification but are not informative for reproducibility. We show that mapped, exonic, non-duplicate (MEND) reads are a useful measure of reproducibility of RNA-Seq datasets used for gene expression analysis.
    Findings: In bulk RNA-Seq datasets from 2,179 tumors in 48 cohorts, the fraction of reads that contribute to the reproducibility of gene expression analysis varies greatly. Unmapped reads constitute 1-77% of all reads (median [IQR], 3% [3-6%]); duplicate reads constitute 3-100% of mapped reads (median [IQR], 27% [13-43%]); and non-exonic reads constitute 4-97% of mapped, non-duplicate reads (median [IQR], 25% [16-37%]). MEND reads constitute 0-79% of total reads (median [IQR], 50% [30-61%]).
    Conclusions: Because not all reads in an RNA-Seq dataset are informative for reproducibility of gene expression measurements and the fraction of reads that are informative varies, we propose reporting a dataset's sequencing depth in MEND reads, which definitively inform the reproducibility of gene expression, rather than total, mapped, or exonic reads. We provide a Docker image containing (i) the existing required tools (RSeQC, sambamba, and samblaster) and (ii) a custom script to calculate MEND reads from RNA-Seq data files. We recommend that all RNA-Seq gene expression experiments, sensitivity studies, and depth recommendations use MEND units for sequencing depth.
    MeSH term(s) Child ; Gene Expression Profiling ; High-Throughput Nucleotide Sequencing ; Humans ; Neoplasms/genetics ; RNA ; Reproducibility of Results ; Sequence Analysis, RNA ; Whole Exome Sequencing
    Chemical Substances RNA (63231-63-0)
    Language English
    Publishing date 2021-02-06
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2708999-X
    ISSN 2047-217X ; 2047-217X
    ISSN (online) 2047-217X
    ISSN 2047-217X
    DOI 10.1093/gigascience/giab011
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Identification of a differentiation stall in epithelial mesenchymal transition in histone H3-mutant diffuse midline glioma.

    Sanders, Lauren M / Cheney, Allison / Seninge, Lucas / van den Bout, Anouk / Chen, Marissa / Beale, Holly C / Kephart, Ellen Towle / Pfeil, Jacob / Learned, Katrina / Lyle, A Geoffrey / Bjork, Isabel / Haussler, David / Salama, Sofie R / Vaske, Olena M

    GigaScience

    2020  Volume 9, Issue 12

    Abstract: Background: Diffuse midline gliomas with histone H3 K27M (H3K27M) mutations occur in early childhood and are marked by an invasive phenotype and global decrease in H3K27me3, an epigenetic mark that regulates differentiation and development. H3K27M ... ...

    Abstract Background: Diffuse midline gliomas with histone H3 K27M (H3K27M) mutations occur in early childhood and are marked by an invasive phenotype and global decrease in H3K27me3, an epigenetic mark that regulates differentiation and development. H3K27M mutation timing and effect on early embryonic brain development are not fully characterized.
    Results: We analyzed multiple publicly available RNA sequencing datasets to identify differentially expressed genes between H3K27M and non-K27M pediatric gliomas. We found that genes involved in the epithelial-mesenchymal transition (EMT) were significantly overrepresented among differentially expressed genes. Overall, the expression of pre-EMT genes was increased in the H3K27M tumors as compared to non-K27M tumors, while the expression of post-EMT genes was decreased. We hypothesized that H3K27M may contribute to gliomagenesis by stalling an EMT required for early brain development, and evaluated this hypothesis by using another publicly available dataset of single-cell and bulk RNA sequencing data from developing cerebral organoids. This analysis revealed similarities between H3K27M tumors and pre-EMT normal brain cells. Finally, a previously published single-cell RNA sequencing dataset of H3K27M and non-K27M gliomas revealed subgroups of cells at different stages of EMT. In particular, H3.1K27M tumors resemble a later EMT stage compared to H3.3K27M tumors.
    Conclusions: Our data analyses indicate that this mutation may be associated with a differentiation stall evident from the failure to proceed through the EMT-like developmental processes, and that H3K27M cells preferentially exist in a pre-EMT cell phenotype. This study demonstrates how novel biological insights could be derived from combined analysis of several previously published datasets, highlighting the importance of making genomic data available to the community in a timely manner.
    MeSH term(s) Cell Differentiation/genetics ; Child ; Child, Preschool ; Epithelial-Mesenchymal Transition/genetics ; Glioma/genetics ; Histones/genetics ; Humans ; Mutation
    Chemical Substances Histones
    Language English
    Publishing date 2020-12-15
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2708999-X
    ISSN 2047-217X ; 2047-217X
    ISSN (online) 2047-217X
    ISSN 2047-217X
    DOI 10.1093/gigascience/giaa136
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: A Functional Precision Medicine Pipeline Combines Comparative Transcriptomics and Tumor Organoid Modeling to Identify Bespoke Treatment Strategies for Glioblastoma.

    Reed, Megan R / Lyle, A Geoffrey / De Loose, Annick / Maddukuri, Leena / Learned, Katrina / Beale, Holly C / Kephart, Ellen T / Cheney, Allison / van den Bout, Anouk / Lee, Madison P / Hundley, Kelsey N / Smith, Ashley M / DesRochers, Teresa M / Vibat, Cecile Rose T / Gokden, Murat / Salama, Sofie / Wardell, Christopher P / Eoff, Robert L / Vaske, Olena M /
    Rodriguez, Analiz

    Cells

    2021  Volume 10, Issue 12

    Abstract: Li Fraumeni syndrome (LFS) is a hereditary cancer predisposition syndrome caused by germline mutations in TP53. TP53 is the most common mutated gene in human cancer, occurring in 30-50% of glioblastomas (GBM). Here, we highlight a precision medicine ... ...

    Abstract Li Fraumeni syndrome (LFS) is a hereditary cancer predisposition syndrome caused by germline mutations in TP53. TP53 is the most common mutated gene in human cancer, occurring in 30-50% of glioblastomas (GBM). Here, we highlight a precision medicine platform to identify potential targets for a GBM patient with LFS. We used a comparative transcriptomics approach to identify genes that are uniquely overexpressed in the LFS GBM patient relative to a cancer compendium of 12,747 tumor RNA sequencing data sets, including 200 GBMs. STAT1 and STAT2 were identified as being significantly overexpressed in the LFS patient, indicating ruxolitinib, a Janus kinase 1 and 2 inhibitors, as a potential therapy. The LFS patient had the highest level of STAT1 and STAT2 expression in an institutional high-grade glioma cohort of 45 patients, further supporting the cancer compendium results. To empirically validate the comparative transcriptomics pipeline, we used a combination of adherent and organoid cell culture techniques, including ex vivo patient-derived organoids (PDOs) from four patient-derived cell lines, including the LFS patient. STAT1 and STAT2 expression levels in the four patient-derived cells correlated with levels identified in the respective parent tumors. In both adherent and organoid cultures, cells from the LFS patient were among the most sensitive to ruxolitinib compared to patient-derived cells with lower STAT1 and STAT2 expression levels. A spheroid-based drug screening assay (3D-PREDICT) was performed and used to identify further therapeutic targets. Two targeted therapies were selected for the patient of interest and resulted in radiographic disease stability. This manuscript supports the use of comparative transcriptomics to identify personalized therapeutic targets in a functional precision medicine platform for malignant brain tumors.
    MeSH term(s) Adolescent ; Adult ; Child ; Female ; Gene Expression Regulation, Neoplastic ; Germ-Line Mutation/genetics ; Glioblastoma/complications ; Glioblastoma/genetics ; Glioblastoma/pathology ; Humans ; Janus Kinase 1/antagonists & inhibitors ; Janus Kinase 1/genetics ; Janus Kinase 2/antagonists & inhibitors ; Janus Kinase 2/genetics ; Li-Fraumeni Syndrome/complications ; Li-Fraumeni Syndrome/genetics ; Li-Fraumeni Syndrome/pathology ; Male ; Nitriles/pharmacology ; Organoids/metabolism ; Precision Medicine ; Pyrazoles/pharmacology ; Pyrimidines/pharmacology ; RNA-Seq ; STAT1 Transcription Factor/genetics ; STAT2 Transcription Factor/genetics ; Transcriptome/genetics ; Young Adult
    Chemical Substances Nitriles ; Pyrazoles ; Pyrimidines ; STAT1 Transcription Factor ; STAT1 protein, human ; STAT2 Transcription Factor ; STAT2 protein, human ; ruxolitinib (82S8X8XX8H) ; Janus Kinase 1 (EC 2.7.10.2) ; Janus Kinase 2 (EC 2.7.10.2)
    Language English
    Publishing date 2021-12-02
    Publishing country Switzerland
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2661518-6
    ISSN 2073-4409 ; 2073-4409
    ISSN (online) 2073-4409
    ISSN 2073-4409
    DOI 10.3390/cells10123400
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Hydra: A mixture modeling framework for subtyping pediatric cancer cohorts using multimodal gene expression signatures.

    Pfeil, Jacob / Sanders, Lauren M / Anastopoulos, Ioannis / Lyle, A Geoffrey / Weinstein, Alana S / Xue, Yuanqing / Blair, Andrew / Beale, Holly C / Lee, Alex / Leung, Stanley G / Dinh, Phuong T / Shah, Avanthi Tayi / Breese, Marcus R / Devine, W Patrick / Bjork, Isabel / Salama, Sofie R / Sweet-Cordero, E Alejandro / Haussler, David / Vaske, Olena Morozova

    PLoS computational biology

    2020  Volume 16, Issue 4, Page(s) e1007753

    Abstract: Precision oncology has primarily relied on coding mutations as biomarkers of response to therapies. While transcriptome analysis can provide valuable information, incorporation into workflows has been difficult. For example, the relative rather than ... ...

    Abstract Precision oncology has primarily relied on coding mutations as biomarkers of response to therapies. While transcriptome analysis can provide valuable information, incorporation into workflows has been difficult. For example, the relative rather than absolute gene expression level needs to be considered, requiring differential expression analysis across samples. However, expression programs related to the cell-of-origin and tumor microenvironment effects confound the search for cancer-specific expression changes. To address these challenges, we developed an unsupervised clustering approach for discovering differential pathway expression within cancer cohorts using gene expression measurements. The hydra approach uses a Dirichlet process mixture model to automatically detect multimodally distributed genes and expression signatures without the need for matched normal tissue. We demonstrate that the hydra approach is more sensitive than widely-used gene set enrichment approaches for detecting multimodal expression signatures. Application of the hydra analysis framework to small blue round cell tumors (including rhabdomyosarcoma, synovial sarcoma, neuroblastoma, Ewing sarcoma, and osteosarcoma) identified expression signatures associated with changes in the tumor microenvironment. The hydra approach also identified an association between ATRX deletions and elevated immune marker expression in high-risk neuroblastoma. Notably, hydra analysis of all small blue round cell tumors revealed similar subtypes, characterized by changes to infiltrating immune and stromal expression signatures.
    MeSH term(s) Biomarkers, Tumor ; Child ; Cluster Analysis ; Computational Biology/methods ; Gene Expression Profiling/methods ; Gene Expression Regulation, Neoplastic/genetics ; Humans ; Models, Statistical ; Neoplasms/genetics ; Neuroblastoma/genetics ; Precision Medicine/methods ; Transcriptome/genetics ; Tumor Microenvironment/genetics
    Chemical Substances Biomarkers, Tumor
    Language English
    Publishing date 2020-04-10
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2193340-6
    ISSN 1553-7358 ; 1553-734X
    ISSN (online) 1553-7358
    ISSN 1553-734X
    DOI 10.1371/journal.pcbi.1007753
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Comparative RNA-seq analysis aids in diagnosis of a rare pediatric tumor.

    Sanders, Lauren M / Rangaswami, Arun / Bjork, Isabel / Lam, Du Linh / Beale, Holly C / Kephart, Ellen Towle / Durbin, Ann / Learned, Katrina / Currie, Rob / Lyle, A Geoffrey / Pfeil, Jacob / Shah, Avanthi Tayi / Lee, Alex G / Leung, Stanley G / Behroozfard, Inge H / Breese, Marcus R / Peralez, Jennifer / Hazard, Florette K / Lacayo, Norman /
    Spunt, Sheri L / Haussler, David / Salama, Sofie R / Sweet-Cordero, E Alejandro / Vaske, Olena M

    Cold Spring Harbor molecular case studies

    2019  Volume 5, Issue 5

    Abstract: Gliomatosis peritonei is a rare pathologic finding that is associated with ovarian teratomas and malignant mixed germ cell tumors. The occurrence of gliomatosis as a mature glial implant can impart an improved prognosis to patients with immature ovarian ... ...

    Abstract Gliomatosis peritonei is a rare pathologic finding that is associated with ovarian teratomas and malignant mixed germ cell tumors. The occurrence of gliomatosis as a mature glial implant can impart an improved prognosis to patients with immature ovarian teratoma, making prompt and accurate diagnosis important. We describe a case of recurrent immature teratoma in a 10-yr-old female patient, in which comparative analysis of the RNA sequencing gene expression data from the patient's tumor was used effectively to aid in the diagnosis of gliomatosis peritonei.
    MeSH term(s) Base Sequence/genetics ; Child ; Female ; Glioma/diagnosis ; Glioma/genetics ; Humans ; Ovarian Neoplasms/diagnosis ; Ovarian Neoplasms/genetics ; Peritoneal Neoplasms/diagnosis ; Peritoneal Neoplasms/genetics ; Prognosis ; RNA-Seq/methods ; Rare Diseases/diagnosis ; Rare Diseases/genetics ; Sequence Analysis, RNA/methods ; Teratoma/diagnosis ; Teratoma/genetics ; Whole Exome Sequencing
    Language English
    Publishing date 2019-10-23
    Publishing country United States
    Document type Case Reports ; Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 2835759-0
    ISSN 2373-2873 ; 2373-2873
    ISSN (online) 2373-2873
    ISSN 2373-2873
    DOI 10.1101/mcs.a004317
    Database MEDical Literature Analysis and Retrieval System OnLINE

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