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4 results on '"Dumenil T"'

1. BET inhibition blocks inflammation-induced cardiac dysfunction and SARS-CoV-2 infection.

Author

Mills R.J., Zhao W., Lee L., Mackenzie-Kludas C., Mehdiabadi N.R., Halliday C., Gilham D., Fu L., Nicholls S.J., Johansson J., Sweeney M., Wong N.C.W., Kulikowski E., Sokolowski K.A., Tse B.W.C., Devilee L., Voges H.K., Reynolds L.T., Krumeich S., Mathieson E., Abu-Bonsrah D., Karavendzas K., Griffen B., Titmarsh D., Elliott D.A., Suhrbier A., Subbarao K., Porrello E.R., Smyth M.J., Engwerda C.R., MacDonald K.P.A., Bald T., James D.E., Hudson J.E., McMahon J., Le T., Humphrey S.J., Fortuna P.R.J., Lor M., Foster S.R., Quaife-Ryan G.A., Johnston R.L., Dumenil T., Bishop C., Rudraraju R., Rawle D.J., Mills R.J., Zhao W., Lee L., Mackenzie-Kludas C., Mehdiabadi N.R., Halliday C., Gilham D., Fu L., Nicholls S.J., Johansson J., Sweeney M., Wong N.C.W., Kulikowski E., Sokolowski K.A., Tse B.W.C., Devilee L., Voges H.K., Reynolds L.T., Krumeich S., Mathieson E., Abu-Bonsrah D., Karavendzas K., Griffen B., Titmarsh D., Elliott D.A., Suhrbier A., Subbarao K., Porrello E.R., Smyth M.J., Engwerda C.R., MacDonald K.P.A., Bald T., James D.E., Hudson J.E., McMahon J., Le T., Humphrey S.J., Fortuna P.R.J., Lor M., Foster S.R., Quaife-Ryan G.A., Johnston R.L., Dumenil T., Bishop C., Rudraraju R., and Rawle D.J.

Abstract

Cardiac injury and dysfunction occur in COVID-19 patients and increase the risk of mortality. Causes are ill defined but could be through direct cardiac infection and/or inflammation-induced dysfunction. To identify mechanisms and cardio-protective drugs, we use a state-of-the-art pipeline combining human cardiac organoids with phosphoproteomics and single nuclei RNA sequencing. We identify an inflammatory "cytokine-storm", a cocktail of interferon gamma, interleukin 1beta, and poly(I:C), induced diastolic dysfunction. Bromodomain-containing protein 4 is activated along with a viral response that is consistent in both human cardiac organoids (hCOs) and hearts of SARS-CoV-2-infected K18-hACE2 mice. Bromodomain and extraterminal family inhibitors (BETi) recover dysfunction in hCOs and completely prevent cardiac dysfunction and death in a mouse cytokine-storm model. Additionally, BETi decreases transcription of genes in the viral response, decreases ACE2 expression, and reduces SARS-CoV-2 infection of cardiomyocytes. Together, BETi, including the Food and Drug Administration (FDA) breakthrough designated drug, apabetalone, are promising candidates to prevent COVID-19 mediated cardiac damage.Copyright © 2021 Elsevier Inc.

Published
2021

2. BET inhibition blocks inflammation-induced cardiac dysfunction and SARS-CoV-2 infection.

Author

Mills R.J., Zhao W., Lee L., Mackenzie-Kludas C., Mehdiabadi N.R., Halliday C., Gilham D., Fu L., Nicholls S.J., Johansson J., Sweeney M., Wong N.C.W., Kulikowski E., Sokolowski K.A., Tse B.W.C., Devilee L., Voges H.K., Reynolds L.T., Krumeich S., Mathieson E., Abu-Bonsrah D., Karavendzas K., Griffen B., Titmarsh D., Elliott D.A., Suhrbier A., Subbarao K., Porrello E.R., Smyth M.J., Engwerda C.R., MacDonald K.P.A., Bald T., James D.E., Hudson J.E., McMahon J., Le T., Humphrey S.J., Fortuna P.R.J., Lor M., Foster S.R., Quaife-Ryan G.A., Johnston R.L., Dumenil T., Bishop C., Rudraraju R., Rawle D.J., Mills R.J., Zhao W., Lee L., Mackenzie-Kludas C., Mehdiabadi N.R., Halliday C., Gilham D., Fu L., Nicholls S.J., Johansson J., Sweeney M., Wong N.C.W., Kulikowski E., Sokolowski K.A., Tse B.W.C., Devilee L., Voges H.K., Reynolds L.T., Krumeich S., Mathieson E., Abu-Bonsrah D., Karavendzas K., Griffen B., Titmarsh D., Elliott D.A., Suhrbier A., Subbarao K., Porrello E.R., Smyth M.J., Engwerda C.R., MacDonald K.P.A., Bald T., James D.E., Hudson J.E., McMahon J., Le T., Humphrey S.J., Fortuna P.R.J., Lor M., Foster S.R., Quaife-Ryan G.A., Johnston R.L., Dumenil T., Bishop C., Rudraraju R., and Rawle D.J.

Abstract

Cardiac injury and dysfunction occur in COVID-19 patients and increase the risk of mortality. Causes are ill defined but could be through direct cardiac infection and/or inflammation-induced dysfunction. To identify mechanisms and cardio-protective drugs, we use a state-of-the-art pipeline combining human cardiac organoids with phosphoproteomics and single nuclei RNA sequencing. We identify an inflammatory "cytokine-storm", a cocktail of interferon gamma, interleukin 1beta, and poly(I:C), induced diastolic dysfunction. Bromodomain-containing protein 4 is activated along with a viral response that is consistent in both human cardiac organoids (hCOs) and hearts of SARS-CoV-2-infected K18-hACE2 mice. Bromodomain and extraterminal family inhibitors (BETi) recover dysfunction in hCOs and completely prevent cardiac dysfunction and death in a mouse cytokine-storm model. Additionally, BETi decreases transcription of genes in the viral response, decreases ACE2 expression, and reduces SARS-CoV-2 infection of cardiomyocytes. Together, BETi, including the Food and Drug Administration (FDA) breakthrough designated drug, apabetalone, are promising candidates to prevent COVID-19 mediated cardiac damage.Copyright © 2021 Elsevier Inc.

Published
2021

3. Contribution of mRNA Splicing to Mismatch Repair Gene Sequence Variant Interpretation.

Author

Thompson, BA, Walters, R, Parsons, MT, Dumenil, T, Drost, M, Tiersma, Y, Lindor, NM, Tavtigian, SV, de Wind, N, Spurdle, AB, InSiGHT Variant Interpretation Committee, Thompson, BA, Walters, R, Parsons, MT, Dumenil, T, Drost, M, Tiersma, Y, Lindor, NM, Tavtigian, SV, de Wind, N, Spurdle, AB, and InSiGHT Variant Interpretation Committee

Abstract

Functional assays that assess mRNA splicing can be used in interpretation of the clinical significance of sequence variants, including the Lynch syndrome-associated mismatch repair (MMR) genes. The purpose of this study was to investigate the contribution of splicing assay data to the classification of MMR gene sequence variants. We assayed mRNA splicing for 24 sequence variants in MLH1, MSH2, and MSH6, including 12 missense variants that were also assessed using a cell-free in vitro MMR activity (CIMRA) assay. Multifactorial likelihood analysis was conducted for each variant, combining CIMRA outputs and clinical data where available. We collated these results with existing public data to provide a dataset of splicing assay results for a total of 671 MMR gene sequence variants (328 missense/in-frame indel), and published and unpublished repair activity measurements for 154 of these variants. There were 241 variants for which a splicing aberration was detected: 92 complete impact, 33 incomplete impact, and 116 where it was not possible to determine complete versus incomplete splicing impact. Splicing results mostly aided in the interpretation of intronic (72%) and silent (92%) variants and were the least useful for missense substitutions/in-frame indels (10%). MMR protein functional activity assays were more useful in the analysis of these exonic variants but by design they were not able to detect clinically important splicing aberrations identified by parallel mRNA assays. The development of high throughput assays that can quantitatively assess impact on mRNA transcript expression and protein function in parallel will streamline classification of MMR gene sequence variants.

Published
2020

4. Contribution of mRNA Splicing to Mismatch Repair Gene Sequence Variant Interpretation.

Author

Thompson, BA, Walters, R, Parsons, MT, Dumenil, T, Drost, M, Tiersma, Y, Lindor, NM, Tavtigian, SV, de Wind, N, Spurdle, AB, InSiGHT Variant Interpretation Committee, Thompson, BA, Walters, R, Parsons, MT, Dumenil, T, Drost, M, Tiersma, Y, Lindor, NM, Tavtigian, SV, de Wind, N, Spurdle, AB, and InSiGHT Variant Interpretation Committee

Abstract

Functional assays that assess mRNA splicing can be used in interpretation of the clinical significance of sequence variants, including the Lynch syndrome-associated mismatch repair (MMR) genes. The purpose of this study was to investigate the contribution of splicing assay data to the classification of MMR gene sequence variants. We assayed mRNA splicing for 24 sequence variants in MLH1, MSH2, and MSH6, including 12 missense variants that were also assessed using a cell-free in vitro MMR activity (CIMRA) assay. Multifactorial likelihood analysis was conducted for each variant, combining CIMRA outputs and clinical data where available. We collated these results with existing public data to provide a dataset of splicing assay results for a total of 671 MMR gene sequence variants (328 missense/in-frame indel), and published and unpublished repair activity measurements for 154 of these variants. There were 241 variants for which a splicing aberration was detected: 92 complete impact, 33 incomplete impact, and 116 where it was not possible to determine complete versus incomplete splicing impact. Splicing results mostly aided in the interpretation of intronic (72%) and silent (92%) variants and were the least useful for missense substitutions/in-frame indels (10%). MMR protein functional activity assays were more useful in the analysis of these exonic variants but by design they were not able to detect clinically important splicing aberrations identified by parallel mRNA assays. The development of high throughput assays that can quantitatively assess impact on mRNA transcript expression and protein function in parallel will streamline classification of MMR gene sequence variants.

Published
2020

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