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  1. Article ; Online: Birinapant selectively enhances immunotoxin-mediated killing of cancer cells conditional on the IAP protein levels within target cells.

    Antignani, Antonella / Bilotta, Maria Teresa / Roth, Jacob S / Urban, Daniel J / Shen, Min / Hall, Matthew D / FitzGerald, David

    FASEB journal : official publication of the Federation of American Societies for Experimental Biology

    2023  Volume 37, Issue 12, Page(s) e23292

    Abstract: Immunotoxins (ITs) target cancer cells via antibody binding to surface antigens followed by internalization and toxin-mediated inhibition of protein synthesis. The fate of cells responding to IT treatment depends on the amount and stability of specific ... ...

    Abstract Immunotoxins (ITs) target cancer cells via antibody binding to surface antigens followed by internalization and toxin-mediated inhibition of protein synthesis. The fate of cells responding to IT treatment depends on the amount and stability of specific pro-apoptotic and pro-survival proteins. When treated with a pseudomonas exotoxin-based immunotoxin (HB21PE40), the triple-negative breast cancer (TNBC) cell line MDA-MB-468 displayed a notable resistance to toxin-mediated killing compared to the epidermoid carcinoma cell line, A431, despite succumbing to the same level of protein synthesis inhibition. In a combination screen of ~1912 clinically relevant and mechanistically annotated compounds, we identified several agents that greatly enhanced IT-mediated killing of MDA-MB-468 cells while exhibiting only a modest enhancement for A431 cells. Of interest, two Smac mimetics, birinapant and SM164, exhibited this kind of differential enhancement. To investigate the basis for this, we probed cells for the presence of inhibitor of apoptosis (IAP) proteins and monitored their stability after the addition of immunotoxin. We found that high levels of IAPs inhibited immunotoxin-mediated cell death. Further, TNFα levels were not relevant for the combination's efficacy. In tumor xenograft studies, combinations of immunotoxin and birinapant caused complete regressions in MDA-MB-468tumor-bearing mice but not in mice with A431 tumors. We propose that IAPs constitute a barrier to immunotoxin efficacy which can be overcome with combination treatments that include Smac mimetics.
    MeSH term(s) Humans ; Animals ; Mice ; Inhibitor of Apoptosis Proteins/metabolism ; Immunotoxins/pharmacology ; Cell Line, Tumor ; Dipeptides/pharmacology ; Apoptosis ; Neoplasms
    Chemical Substances Inhibitor of Apoptosis Proteins ; birinapant (6O4Z07B57R) ; Immunotoxins ; Dipeptides
    Language English
    Publishing date 2023-11-16
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Intramural
    ZDB-ID 639186-2
    ISSN 1530-6860 ; 0892-6638
    ISSN (online) 1530-6860
    ISSN 0892-6638
    DOI 10.1096/fj.202301052R
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 2266: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)
    Zs.MO 296: Show issues

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  2. Article ; Online: Type I and II PRMTs inversely regulate post-transcriptional intron detention through Sm and CHTOP methylation.

    Maron, Maxim I / Casill, Alyssa D / Gupta, Varun / Roth, Jacob S / Sidoli, Simone / Query, Charles C / Gamble, Matthew J / Shechter, David

    eLife

    2022  Volume 11

    Abstract: Protein arginine methyltransferases (PRMTs) are required for the regulation of RNA processing factors. Type I PRMT enzymes catalyze mono- and asymmetric dimethylation; Type II enzymes catalyze mono- and symmetric dimethylation. To understand the specific ...

    Abstract Protein arginine methyltransferases (PRMTs) are required for the regulation of RNA processing factors. Type I PRMT enzymes catalyze mono- and asymmetric dimethylation; Type II enzymes catalyze mono- and symmetric dimethylation. To understand the specific mechanisms of PRMT activity in splicing regulation, we inhibited Type I and II PRMTs and probed their transcriptomic consequences. Using the newly developed Splicing Kinetics and Transcript Elongation Rates by Sequencing (SKaTER-seq) method, analysis of co-transcriptional splicing demonstrated that PRMT inhibition resulted in altered splicing rates. Surprisingly, co-transcriptional splicing kinetics did not correlate with final changes in splicing of polyadenylated RNA. This was particularly true for retained introns (RI). By using actinomycin D to inhibit ongoing transcription, we determined that PRMTs post-transcriptionally regulate RI. Subsequent proteomic analysis of both PRMT-inhibited chromatin and chromatin-associated polyadenylated RNA identified altered binding of many proteins, including the Type I substrate, CHTOP, and the Type II substrate, SmB. Targeted mutagenesis of all methylarginine sites in SmD3, SmB, and SmD1 recapitulated splicing changes seen with Type II PRMT inhibition, without disrupting snRNP assembly. Similarly, mutagenesis of all methylarginine sites in CHTOP recapitulated the splicing changes seen with Type I PRMT inhibition. Examination of subcellular fractions further revealed that RI were enriched in the nucleoplasm and chromatin. Taken together, these data demonstrate that, through Sm and CHTOP arginine methylation, PRMTs regulate the post-transcriptional processing of nuclear, detained introns.
    MeSH term(s) Cell Line ; Gene Expression Regulation ; Humans ; Introns/genetics ; Methylation ; Nuclear Proteins/genetics ; Nuclear Proteins/metabolism ; Protein-Arginine N-Methyltransferases/genetics ; Protein-Arginine N-Methyltransferases/metabolism ; Transcription Factors/genetics ; Transcription Factors/metabolism ; snRNP Core Proteins/genetics ; snRNP Core Proteins/metabolism
    Chemical Substances CHTOP protein, human ; Nuclear Proteins ; SNRPB protein, human ; Transcription Factors ; snRNP Core Proteins ; Protein-Arginine N-Methyltransferases (EC 2.1.1.319)
    Language English
    Publishing date 2022-01-05
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2687154-3
    ISSN 2050-084X ; 2050-084X
    ISSN (online) 2050-084X
    ISSN 2050-084X
    DOI 10.7554/eLife.72867
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article: Correction to Remdesivir: A Review of Its Discovery and Development Leading to Human Clinical Trials for Treatment of COVID-19.

    Eastman, Richard T / Roth, Jacob S / Brimacombe, Kyle R / Simeonov, Anton / Shen, Min / Patnaik, Samarjit / Hall, Matthew D

    ACS central science

    2020  Volume 6, Issue 6, Page(s) 1009

    Abstract: This corrects the article DOI: 10.1021/acscentsci.0c00489.]. ...

    Abstract [This corrects the article DOI: 10.1021/acscentsci.0c00489.].
    Keywords covid19
    Language English
    Publishing date 2020-06-16
    Publishing country United States
    Document type Journal Article ; Published Erratum
    ISSN 2374-7943
    ISSN 2374-7943
    DOI 10.1021/acscentsci.0c00747
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article: Remdesivir: A Review of Its Discovery and Development Leading to Emergency Use Authorization for Treatment of COVID-19.

    Eastman, Richard T / Roth, Jacob S / Brimacombe, Kyle R / Simeonov, Anton / Shen, Min / Patnaik, Samarjit / Hall, Matthew D

    ACS central science

    2020  Volume 6, Issue 5, Page(s) 672–683

    Abstract: The global pandemic of SARS-CoV-2, the causative viral pathogen of COVID-19, has driven the biomedical community to action-to uncover and develop antiviral interventions. One potential therapeutic approach currently being evaluated in numerous clinical ... ...

    Abstract The global pandemic of SARS-CoV-2, the causative viral pathogen of COVID-19, has driven the biomedical community to action-to uncover and develop antiviral interventions. One potential therapeutic approach currently being evaluated in numerous clinical trials is the agent remdesivir, which has endured a long and winding developmental path. Remdesivir is a nucleotide analogue prodrug that perturbs viral replication, originally evaluated in clinical trials to thwart the Ebola outbreak in 2014. Subsequent evaluation by numerous virology laboratories demonstrated the ability of remdesivir to inhibit coronavirus replication, including SARS-CoV-2. Here, we provide an overview of remdesivir's discovery, mechanism of action, and the current studies exploring its clinical effectiveness.
    Keywords covid19
    Language English
    Publishing date 2020-05-04
    Publishing country United States
    Document type Journal Article ; Review
    ISSN 2374-7943
    ISSN 2374-7943
    DOI 10.1021/acscentsci.0c00489
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article: Correction to Remdesivir: A Review of Its Discovery and Development Leading to Human Clinical Trials for Treatment of COVID-19

    Eastman, Richard T / Roth, Jacob S / Brimacombe, Kyle R / Simeonov, Anton / Shen, Min / Patnaik, Samarjit / Hall, Matthew D

    ACS Cent Sci

    Abstract: This corrects the article DOI: 10.1021/acscentsci.0c00489.]. ...

    Abstract [This corrects the article DOI: 10.1021/acscentsci.0c00489.].
    Keywords covid19
    Publisher WHO
    Document type Article
    Note WHO #Covidence: #606650
    Database COVID19

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  6. Article: Remdesivir: A Review of Its Discovery and Development Leading to Emergency Use Authorization for Treatment of COVID-19

    Eastman, Richard T. / Roth, Jacob S. / Brimacombe, Kyle R. / Simeonov, Anton / Shen, Min / Patnaik, Samarjit / Hall, Matthew D.

    ACS Cent. Sci.

    Abstract: The global pandemic of SARS-CoV-2, the causative viral pathogen of COVID-19, has driven the biomedical community to action - to uncover and develop antiviral interventions. One potential therapeutic approach currently being evaluated in numerous clinical ...

    Abstract The global pandemic of SARS-CoV-2, the causative viral pathogen of COVID-19, has driven the biomedical community to action - to uncover and develop antiviral interventions. One potential therapeutic approach currently being evaluated in numerous clinical trials is the agent remdesivir, which has endured a long and winding developmental path. Remdesivir is a nucleotide analogue prodrug that perturbs viral replication, originally evaluated in clinical trials to thwart the Ebola outbreak in 2014. Subsequent evaluation by numerous virology laboratories demonstrated the ability of remdesivir to inhibit coronavirus replication, including SARS-CoV-2. Here, we provide an overview of remdesivir's discovery, mechanism of action, and the current studies exploring its clinical effectiveness.
    Keywords covid19
    Publisher WHO
    Document type Article
    Note WHO #Covidence: #165123
    Database COVID19

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  7. Article ; Online: Remdesivir

    Eastman, Richard T. / Roth, Jacob S. / Brimacombe, Kyle R. / Simeonov, Anton / Shen, Min / Patnaik, Samarjit / Hall, Matthew D.

    ACS Central Science

    A Review of Its Discovery and Development Leading to Emergency Use Authorization for Treatment of COVID-19

    2020  Volume 6, Issue 5, Page(s) 672–683

    Keywords covid19
    Language English
    Publisher American Chemical Society (ACS)
    Publishing country us
    Document type Article ; Online
    ISSN 2374-7943
    DOI 10.1021/acscentsci.0c00489
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  8. Article ; Online: Correction to Remdesivir

    Eastman, Richard T. / Roth, Jacob S. / Brimacombe, Kyle R. / Simeonov, Anton / Shen, Min / Patnaik, Samarjit / Hall, Matthew D.

    ACS Central Science

    A Review of Its Discovery and Development Leading to Human Clinical Trials for Treatment of COVID-19

    2020  Volume 6, Issue 6, Page(s) 1009–1009

    Keywords covid19
    Language English
    Publisher American Chemical Society (ACS)
    Publishing country us
    Document type Article ; Online
    ISSN 2374-7943
    DOI 10.1021/acscentsci.0c00747
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

    Full text online

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  9. Article ; Online: Keeping It Clean: The Cell Culture Quality Control Experience at the National Center for Advancing Translational Sciences.

    Roth, Jacob S / Lee, Tobie D / Cheff, Dorian M / Gosztyla, Maya L / Asawa, Rosita R / Danchik, Carina / Michael, Sam / Simeonov, Anton / Klumpp-Thomas, Carleen / Wilson, Kelli M / Hall, Matthew D

    SLAS discovery : advancing life sciences R & D

    2020  Volume 25, Issue 5, Page(s) 491–497

    Abstract: Quality control monitoring of cell lines utilized in biomedical research is of utmost importance and is critical for the reproducibility of data. Two key pitfalls in tissue culture are 1) cell line authenticity and 2) ...

    Abstract Quality control monitoring of cell lines utilized in biomedical research is of utmost importance and is critical for the reproducibility of data. Two key pitfalls in tissue culture are 1) cell line authenticity and 2)
    MeSH term(s) Cell Culture Techniques/methods ; Cell Line, Tumor ; Humans ; Microsatellite Repeats/genetics ; Mycoplasma/isolation & purification ; Mycoplasma/pathogenicity ; National Center for Advancing Translational Sciences (U.S.) ; Polymerase Chain Reaction ; Quality Control ; Translational Research, Biomedical/standards ; Translational Research, Biomedical/trends ; United States/epidemiology
    Language English
    Publishing date 2020-04-01
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Intramural
    ZDB-ID 2885123-7
    ISSN 2472-5560 ; 2472-5552
    ISSN (online) 2472-5560
    ISSN 2472-5552
    DOI 10.1177/2472555220911451
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 4911: 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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  10. Article ; Online: Characterization and tissue localization of zebrafish homologs of the human ABCB1 multidrug transporter.

    Robey, Robert W / Robinson, Andrea N / Ali-Rahmani, Fatima / Huff, Lyn M / Lusvarghi, Sabrina / Vahedi, Shahrooz / Hotz, Jordan M / Warner, Andrew C / Butcher, Donna / Matta, Jennifer / Edmondson, Elijah F / Lee, Tobie D / Roth, Jacob S / Lee, Olivia W / Shen, Min / Tanner, Kandice / Hall, Matthew D / Ambudkar, Suresh V / Gottesman, Michael M

    Scientific reports

    2021  Volume 11, Issue 1, Page(s) 24150

    Abstract: Capillary endothelial cells of the human blood-brain barrier (BBB) express high levels of P-glycoprotein (P-gp, encoded by ABCB1) and ABCG2 (encoded by ABCG2). However, little information is available regarding ATP-binding cassette transporters expressed ...

    Abstract Capillary endothelial cells of the human blood-brain barrier (BBB) express high levels of P-glycoprotein (P-gp, encoded by ABCB1) and ABCG2 (encoded by ABCG2). However, little information is available regarding ATP-binding cassette transporters expressed at the zebrafish BBB, which has emerged as a potential model system. We report the characterization and tissue localization of two genes that are similar to ABCB1, zebrafish abcb4 and abcb5. When stably expressed in HEK293 cells, both Abcb4 and Abcb5 conferred resistance to P-gp substrates; however, Abcb5 poorly transported doxorubicin and mitoxantrone compared to zebrafish Abcb4. Additionally, Abcb5 did not transport the fluorescent P-gp probes BODIPY-ethylenediamine or LDS 751, while they were transported by Abcb4. High-throughput screening of 90 human P-gp substrates confirmed that Abcb4 has an overlapping substrate specificity profile with P-gp. In the brain vasculature, RNAscope probes for abcb4 colocalized with staining by the P-gp antibody C219, while abcb5 was not detected. The abcb4 probe also colocalized with claudin-5 in brain endothelial cells. Abcb4 and Abcb5 had different tissue localizations in multiple zebrafish tissues, potentially indicating different functions. The data suggest that zebrafish Abcb4 functionally phenocopies P-gp and that the zebrafish may serve as a model to study the role of P-gp at the BBB.
    MeSH term(s) ATP Binding Cassette Transporter, Subfamily B/genetics ; ATP Binding Cassette Transporter, Subfamily B/metabolism ; ATP-Binding Cassette Transporters/genetics ; ATP-Binding Cassette Transporters/metabolism ; Animals ; Biological Transport, Active ; Blood-Brain Barrier/metabolism ; Endothelial Cells/metabolism ; HEK293 Cells ; Humans ; Organ Specificity ; Zebrafish/genetics ; Zebrafish/metabolism ; Zebrafish Proteins/genetics ; Zebrafish Proteins/metabolism
    Chemical Substances ABCB1 protein, human ; ATP Binding Cassette Transporter, Subfamily B ; ATP-Binding Cassette Transporters ; Abcb4 protein, zebrafish ; Zebrafish Proteins
    Language English
    Publishing date 2021-12-17
    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/s41598-021-03500-8
    Database MEDical Literature Analysis and Retrieval System OnLINE

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