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  1. Article ; Online: Venetoclax treatment in patients with cancer has limited impact on circulating T and NK cells.

    Teh, Charis E / Peng, Hongke / Luo, Meng-Xiao / Tan, Tania / Trussart, Marie / Howson, Lauren J / Chua, Chong Chyn / Muttiah, Christine / Brown, Fiona / Ritchie, Matthew E / Wei, Andrew H / Roberts, Andrew W / Bryant, Vanessa L / Anderson, Mary Ann / Lindeman, Geoffrey J / Huang, David C S / Thijssen, Rachel / Gray, Daniel H D

    Blood advances

    2022  Volume 7, Issue 12, Page(s) 2733–2745

    Abstract: Venetoclax is an effective treatment for certain blood cancers, such as chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML). However, most patients relapse while on venetoclax and further treatment options are limited. Combining ... ...

    Abstract Venetoclax is an effective treatment for certain blood cancers, such as chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML). However, most patients relapse while on venetoclax and further treatment options are limited. Combining venetoclax with immunotherapies is an attractive approach; however, a detailed understanding of how venetoclax treatment impacts normal immune cells in patients is lacking. In this study, we performed deep profiling of peripheral blood (PB) cells from patients with CLL and AML before and after short-term treatment with venetoclax using mass cytometry (cytometry by time of flight) and found no impact on the concentrations of key T-cell subsets or their expression of checkpoint molecules. We also analyzed PB from patients with breast cancer receiving venetoclax long-term using a single-cell multiomics approach (cellular indexing of transcriptomes and epitopes by sequencing) and functional assays. We found significant depletion of B-cell populations with low expression of MCL-1 relative to other immune cells, attended by extensive transcriptomic changes. By contrast, there was less impact on circulating T cells and natural killer (NK) cells, with no changes in their subset composition, transcriptome, or function following venetoclax treatment. Our data indicate that venetoclax has minimal impact on circulating T or NK cells, supporting the rationale of combining this BH3 mimetic drug with cancer immunotherapies for more durable antitumor responses.
    MeSH term(s) Humans ; Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy ; Killer Cells, Natural ; Leukemia, Myeloid, Acute/drug therapy ; Bridged Bicyclo Compounds, Heterocyclic/pharmacology ; Bridged Bicyclo Compounds, Heterocyclic/therapeutic use
    Chemical Substances venetoclax (N54AIC43PW) ; Bridged Bicyclo Compounds, Heterocyclic
    Language English
    Publishing date 2022-12-14
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2915908-8
    ISSN 2473-9537 ; 2473-9529
    ISSN (online) 2473-9537
    ISSN 2473-9529
    DOI 10.1182/bloodadvances.2022008221
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 7153: Show issues Location:
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  2. Article ; Online: Single-cell multiomics reveal the scale of multilayered adaptations enabling CLL relapse during venetoclax therapy.

    Thijssen, Rachel / Tian, Luyi / Anderson, Mary Ann / Flensburg, Christoffer / Jarratt, Andrew / Garnham, Alexandra L / Jabbari, Jafar S / Peng, Hongke / Lew, Thomas E / Teh, Charis E / Gouil, Quentin / Georgiou, Angela / Tan, Tania / Djajawi, Tirta M / Tam, Constantine S / Seymour, John F / Blombery, Piers / Gray, Daniel H D / Majewski, Ian J /
    Ritchie, Matthew E / Roberts, Andrew W / Huang, David C S

    Blood

    2022  Volume 140, Issue 20, Page(s) 2127–2141

    Abstract: Venetoclax (VEN) inhibits the prosurvival protein BCL2 to induce apoptosis and is a standard therapy for chronic lymphocytic leukemia (CLL), delivering high complete remission rates and prolonged progression-free survival in relapsed CLL but with ... ...

    Abstract Venetoclax (VEN) inhibits the prosurvival protein BCL2 to induce apoptosis and is a standard therapy for chronic lymphocytic leukemia (CLL), delivering high complete remission rates and prolonged progression-free survival in relapsed CLL but with eventual loss of efficacy. A spectrum of subclonal genetic changes associated with VEN resistance has now been described. To fully understand clinical resistance to VEN, we combined single-cell short- and long-read RNA-sequencing to reveal the previously unappreciated scale of genetic and epigenetic changes underpinning acquired VEN resistance. These appear to be multilayered. One layer comprises changes in the BCL2 family of apoptosis regulators, especially the prosurvival family members. This includes previously described mutations in BCL2 and amplification of the MCL1 gene but is heterogeneous across and within individual patient leukemias. Changes in the proapoptotic genes are notably uncommon, except for single cases with subclonal losses of BAX or NOXA. Much more prominent was universal MCL1 gene upregulation. This was driven by an overlying layer of emergent NF-κB (nuclear factor kappa B) activation, which persisted in circulating cells during VEN therapy. We discovered that MCL1 could be a direct transcriptional target of NF-κB. Both the switch to alternative prosurvival factors and NF-κB activation largely dissipate following VEN discontinuation. Our studies reveal the extent of plasticity of CLL cells in their ability to evade VEN-induced apoptosis. Importantly, these findings pinpoint new approaches to circumvent VEN resistance and provide a specific biological justification for the strategy of VEN discontinuation once a maximal response is achieved rather than maintaining long-term selective pressure with the drug.
    MeSH term(s) Humans ; Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy ; Leukemia, Lymphocytic, Chronic, B-Cell/genetics ; Leukemia, Lymphocytic, Chronic, B-Cell/metabolism ; Myeloid Cell Leukemia Sequence 1 Protein/metabolism ; Proto-Oncogene Proteins c-bcl-2/metabolism ; NF-kappa B ; Drug Resistance, Neoplasm/genetics ; Bridged Bicyclo Compounds, Heterocyclic/pharmacology ; Bridged Bicyclo Compounds, Heterocyclic/therapeutic use ; Recurrence ; Antineoplastic Agents/therapeutic use
    Chemical Substances venetoclax (N54AIC43PW) ; Myeloid Cell Leukemia Sequence 1 Protein ; Proto-Oncogene Proteins c-bcl-2 ; NF-kappa B ; Bridged Bicyclo Compounds, Heterocyclic ; Antineoplastic Agents
    Language English
    Publishing date 2022-06-08
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 80069-7
    ISSN 1528-0020 ; 0006-4971
    ISSN (online) 1528-0020
    ISSN 0006-4971
    DOI 10.1182/blood.2022016040
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Uh III Zs.140: Show issues Location:
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    Zs.MO 364: Show issues

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  3. Article ; Online: Epigenetic Silencing of RIPK3 in Hepatocytes Prevents MLKL-mediated Necroptosis From Contributing to Liver Pathologies.

    Preston, Simon P / Stutz, Michael D / Allison, Cody C / Nachbur, Ueli / Gouil, Quentin / Tran, Bang Manh / Duvivier, Valerie / Arandjelovic, Philip / Cooney, James P / Mackiewicz, Liana / Meng, Yanxiang / Schaefer, Jan / Bader, Stefanie M / Peng, Hongke / Valaydon, Zina / Rajasekaran, Pravin / Jennison, Charlie / Lopaticki, Sash / Farrell, Ann /
    Ryan, Marno / Howell, Jess / Croagh, Catherine / Karunakaran, Denuja / Schuster-Klein, Carole / Murphy, James M / Fifis, Theodora / Christophi, Christopher / Vincan, Elizabeth / Blewitt, Marnie E / Thompson, Alexander / Boddey, Justin A / Doerflinger, Marcel / Pellegrini, Marc

    Gastroenterology

    2022  Volume 163, Issue 6, Page(s) 1643–1657.e14

    Abstract: Background & aims: Necroptosis is a highly inflammatory mode of cell death that has been implicated in causing hepatic injury including steatohepatitis/ nonalcoholic steatohepatitis (NASH); however, the evidence supporting these claims has been ... ...

    Abstract Background & aims: Necroptosis is a highly inflammatory mode of cell death that has been implicated in causing hepatic injury including steatohepatitis/ nonalcoholic steatohepatitis (NASH); however, the evidence supporting these claims has been controversial. A comprehensive, fundamental understanding of cell death pathways involved in liver disease critically underpins rational strategies for therapeutic intervention. We sought to define the role and relevance of necroptosis in liver pathology.
    Methods: Several animal models of human liver pathology, including diet-induced steatohepatitis in male mice and diverse infections in both male and female mice, were used to dissect the relevance of necroptosis in liver pathobiology. We applied necroptotic stimuli to primary mouse and human hepatocytes to measure their susceptibility to necroptosis. Paired liver biospecimens from patients with NASH, before and after intervention, were analyzed. DNA methylation sequencing was also performed to investigate the epigenetic regulation of RIPK3 expression in primary human and mouse hepatocytes.
    Results: Identical infection kinetics and pathologic outcomes were observed in mice deficient in an essential necroptotic effector protein, MLKL, compared with control animals. Mice lacking MLKL were indistinguishable from wild-type mice when fed a high-fat diet to induce NASH. Under all conditions tested, we were unable to induce necroptosis in hepatocytes. We confirmed that a critical activator of necroptosis, RIPK3, was epigenetically silenced in mouse and human primary hepatocytes and rendered them unable to undergo necroptosis.
    Conclusions: We have provided compelling evidence that necroptosis is disabled in hepatocytes during homeostasis and in the pathologic conditions tested in this study.
    MeSH term(s) Humans ; Female ; Male ; Mice ; Animals ; Necroptosis ; Epigenesis, Genetic ; Non-alcoholic Fatty Liver Disease/genetics ; Hepatocytes ; Receptor-Interacting Protein Serine-Threonine Kinases/genetics ; Protein Kinases/genetics
    Chemical Substances RIPK3 protein, human (EC 2.7.11.1) ; Receptor-Interacting Protein Serine-Threonine Kinases (EC 2.7.11.1) ; MLKL protein, human (EC 2.7.-) ; Protein Kinases (EC 2.7.-) ; Ripk3 protein, mouse (EC 2.7.11.1) ; MLKL protein, mouse (EC 2.7.-)
    Language English
    Publishing date 2022-08-28
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 80112-4
    ISSN 1528-0012 ; 0016-5085
    ISSN (online) 1528-0012
    ISSN 0016-5085
    DOI 10.1053/j.gastro.2022.08.040
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Ui V Zs.44: Show issues Location:
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    Zs.MO 572: Show issues

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  4. Article ; Online: Comprehensive characterization of single-cell full-length isoforms in human and mouse with long-read sequencing.

    Tian, Luyi / Jabbari, Jafar S / Thijssen, Rachel / Gouil, Quentin / Amarasinghe, Shanika L / Voogd, Oliver / Kariyawasam, Hasaru / Du, Mei R M / Schuster, Jakob / Wang, Changqing / Su, Shian / Dong, Xueyi / Law, Charity W / Lucattini, Alexis / Prawer, Yair David Joseph / Collar-Fernández, Coralina / Chung, Jin D / Naim, Timur / Chan, Audrey /
    Ly, Chi Hai / Lynch, Gordon S / Ryall, James G / Anttila, Casey J A / Peng, Hongke / Anderson, Mary Ann / Flensburg, Christoffer / Majewski, Ian / Roberts, Andrew W / Huang, David C S / Clark, Michael B / Ritchie, Matthew E

    Genome biology

    2021  Volume 22, Issue 1, Page(s) 310

    Abstract: A modified Chromium 10x droplet-based protocol that subsamples cells for both short-read and long-read (nanopore) sequencing together with a new computational pipeline (FLAMES) is developed to enable isoform discovery, splicing analysis, and mutation ... ...

    Abstract A modified Chromium 10x droplet-based protocol that subsamples cells for both short-read and long-read (nanopore) sequencing together with a new computational pipeline (FLAMES) is developed to enable isoform discovery, splicing analysis, and mutation detection in single cells. We identify thousands of unannotated isoforms and find conserved functional modules that are enriched for alternative transcript usage in different cell types and species, including ribosome biogenesis and mRNA splicing. Analysis at the transcript level allows data integration with scATAC-seq on individual promoters, improved correlation with protein expression data, and linked mutations known to confer drug resistance to transcriptome heterogeneity.
    MeSH term(s) Alternative Splicing ; Animals ; Exons ; Gene Expression Profiling/methods ; High-Throughput Nucleotide Sequencing ; Humans ; Mice ; Nanopore Sequencing/methods ; Protein Isoforms/genetics ; Protein Isoforms/metabolism ; RNA Splicing ; RNA, Messenger ; Transcriptome
    Chemical Substances Protein Isoforms ; RNA, Messenger
    Language English
    Publishing date 2021-11-11
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2040529-7
    ISSN 1474-760X ; 1474-760X
    ISSN (online) 1474-760X
    ISSN 1474-760X
    DOI 10.1186/s13059-021-02525-6
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article: Comprehensive characterization of single-cell full-length isoforms in human and mouse with long-read sequencing

    Tian, Luyi / Jabbari, Jafar S. / Thijssen, Rachel / Gouil, Quentin / Amarasinghe, Shanika L. / Voogd, Oliver / Kariyawasam, Hasaru / Du, Mei R. M. / Schuster, Jakob / Wang, Changqing / Su, Shian / Dong, Xueyi / Law, Charity W. / Lucattini, Alexis / Prawer, Yair David Joseph / Collar-Fernández, Coralina / Chung, Jin D. / Naim, Timur / Chan, Audrey /
    Ly, Chi Hai / Lynch, Gordon S. / Ryall, James G. / Anttila, Casey J. A. / Peng, Hongke / Anderson, Mary Ann / Flensburg, Christoffer / Majewski, Ian / Roberts, Andrew W. / Huang, David C. S. / Clark, Michael B. / Ritchie, Matthew E.

    Genome biology. 2021 Dec., v. 22, no. 1

    2021  

    Abstract: A modified Chromium 10x droplet-based protocol that subsamples cells for both short-read and long-read (nanopore) sequencing together with a new computational pipeline (FLAMES) is developed to enable isoform discovery, splicing analysis, and mutation ... ...

    Abstract A modified Chromium 10x droplet-based protocol that subsamples cells for both short-read and long-read (nanopore) sequencing together with a new computational pipeline (FLAMES) is developed to enable isoform discovery, splicing analysis, and mutation detection in single cells. We identify thousands of unannotated isoforms and find conserved functional modules that are enriched for alternative transcript usage in different cell types and species, including ribosome biogenesis and mRNA splicing. Analysis at the transcript level allows data integration with scATAC-seq on individual promoters, improved correlation with protein expression data, and linked mutations known to confer drug resistance to transcriptome heterogeneity.
    Keywords biogenesis ; chromium ; drug resistance ; genome ; humans ; mice ; mutation ; nanopores ; protein synthesis ; ribosomes ; transcriptome
    Language English
    Dates of publication 2021-12
    Size p. 310.
    Publishing place BioMed Central
    Document type Article
    ZDB-ID 2040529-7
    ISSN 1474-760X
    ISSN 1474-760X
    DOI 10.1186/s13059-021-02525-6
    Database NAL-Catalogue (AGRICOLA)

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