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  1. Article ; Online: How CHKing ROS signaling preserves genomic integrity.

    Venkatachalam, Annapoorna / Kaufmann, Scott H

    Cell research

    2023  Volume 33, Issue 11, Page(s) 815–816

    MeSH term(s) Reactive Oxygen Species ; Signal Transduction ; DNA Damage ; Genomics
    Chemical Substances Reactive Oxygen Species
    Language English
    Publishing date 2023-06-29
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Comment
    ZDB-ID 1319303-x
    ISSN 1748-7838 ; 1001-0602
    ISSN (online) 1748-7838
    ISSN 1001-0602
    DOI 10.1038/s41422-023-00840-0
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 5283: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
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    Jg. 1995 - 2021: Lesesall (2.OG)
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  2. Book: Apoptosis

    Kaufmann, Scott H.

    pharmacological implications and therapeutic opportunities

    (Advances in pharmacology ; 41)

    1997  

    Author's details vol. ed. Scott H. Kaufmann
    Series title Advances in pharmacology ; 41
    Collection
    Keywords Apoptosis
    Subject Apoptose ; Programmierter Zelltod
    Size XXV, 614 S. : Ill., graph. Darst.
    Publisher Academic Press
    Publishing place San Diego u.a.
    Publishing country United States
    Document type Book
    HBZ-ID HT007593112
    ISBN 0-12-032942-5 ; 978-0-12-032942-7
    Database Catalogue ZB MED Medicine, Health

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    In stock of ZB MED Cologne/Königswinter

    Shelf markLoan statusLocation
    Uf I Zs 171 -41- verfügbar in Königswinter Königswinter

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  3. Article ; Online: Topoisomerases and cancer chemotherapy: recent advances and unanswered questions.

    Bjornsti, Mary-Ann / Kaufmann, Scott H

    F1000Research

    2019  Volume 8

    Abstract: DNA topoisomerases are enzymes that catalyze changes in the torsional and flexural strain of DNA molecules. Earlier studies implicated these enzymes in a variety of processes in both prokaryotes and eukaryotes, including DNA replication, transcription, ... ...

    Abstract DNA topoisomerases are enzymes that catalyze changes in the torsional and flexural strain of DNA molecules. Earlier studies implicated these enzymes in a variety of processes in both prokaryotes and eukaryotes, including DNA replication, transcription, recombination, and chromosome segregation. Studies performed over the past 3 years have provided new insight into the roles of various topoisomerases in maintaining eukaryotic chromosome structure and facilitating the decatenation of daughter chromosomes at cell division. In addition, recent studies have demonstrated that the incorporation of ribonucleotides into DNA results in trapping of topoisomerase I (TOP1)-DNA covalent complexes during aborted ribonucleotide removal. Importantly, such trapped TOP1-DNA covalent complexes, formed either during ribonucleotide removal or as a consequence of drug action, activate several repair processes, including processes involving the recently described nuclear proteases SPARTAN and GCNA-1. A variety of new TOP1 inhibitors and formulations, including antibody-drug conjugates and PEGylated complexes, exert their anticancer effects by also trapping these TOP1-DNA covalent complexes. Here we review recent developments and identify further questions raised by these new findings.
    MeSH term(s) DNA ; DNA Damage ; DNA Replication ; DNA Topoisomerases/physiology ; Humans ; Neoplasms
    Chemical Substances DNA (9007-49-2) ; DNA Topoisomerases (EC 5.99.1.-)
    Language English
    Publishing date 2019-09-30
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Review
    ZDB-ID 2699932-8
    ISSN 2046-1402 ; 2046-1402
    ISSN (online) 2046-1402
    ISSN 2046-1402
    DOI 10.12688/f1000research.20201.1
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Resistance to venetoclax and hypomethylating agents in acute myeloid leukemia.

    Saliba, Antoine N / John, August J / Kaufmann, Scott H

    Cancer drug resistance (Alhambra, Calif.)

    2021  Volume 4, Page(s) 125–142

    Abstract: Despite the success of the combination of venetoclax with the hypomethylating agents (HMA) decitabine or azacitidine in inducing remission in older, previously untreated patients with acute myeloid leukemia (AML), resistance - primary or secondary - ... ...

    Abstract Despite the success of the combination of venetoclax with the hypomethylating agents (HMA) decitabine or azacitidine in inducing remission in older, previously untreated patients with acute myeloid leukemia (AML), resistance - primary or secondary - still constitutes a significant roadblock in the quest to prolong the duration of response. Here we review the proposed and proven mechanisms of resistance to venetoclax monotherapy, HMA monotherapy, and the doublet of venetoclax and HMA for the treatment of AML. We approach the mechanisms of resistance to HMAs and venetoclax in the light of the agents' mechanisms of action. We briefly describe potential therapeutic strategies to circumvent resistance to this promising combination, including alternative scheduling or the addition of other agents to the HMA and venetoclax backbone. Understanding the mechanisms of action and evolving resistance in AML remains a priority in order to maximize the benefit from novel drugs and combinations, identify new therapeutic targets, define potential prognostic markers, and avoid treatment failure.
    Language English
    Publishing date 2021-03-19
    Publishing country United States
    Document type Journal Article
    ISSN 2578-532X
    ISSN (online) 2578-532X
    DOI 10.20517/cdr.2020.95
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  5. Article ; Online: Selective Inhibition of BFL1: It's All about Finding the Right Partner.

    Dai, Haiming / Meng, X Wei / Kaufmann, Scott H

    Cell chemical biology

    2020  Volume 27, Issue 6, Page(s) 639–642

    Abstract: In this issue of Cell Chemical Biology, Harvey et al. (2020) identify 4E14, a sulfhydryl-containing N-acetyltryptophan analog that selectively disrupts binding to the previously undruggable anti-apoptotic BCL2 paralog BFL1, and elucidate a BFL1 ... ...

    Abstract In this issue of Cell Chemical Biology, Harvey et al. (2020) identify 4E14, a sulfhydryl-containing N-acetyltryptophan analog that selectively disrupts binding to the previously undruggable anti-apoptotic BCL2 paralog BFL1, and elucidate a BFL1 conformational change that facilitates 4E14 interaction. These results provide insight that will accelerate development of BFL1 inhibitors.
    MeSH term(s) Apoptosis ; Cell Death ; Disulfides ; Methylcellulose
    Chemical Substances Disulfides ; Methylcellulose (9004-67-5)
    Language English
    Publishing date 2020-08-28
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Comment
    ISSN 2451-9448
    ISSN (online) 2451-9448
    DOI 10.1016/j.chembiol.2020.05.014
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  6. Article: PARP Inhibitors and Myeloid Neoplasms: A Double-Edged Sword.

    Csizmar, Clifford M / Saliba, Antoine N / Swisher, Elizabeth M / Kaufmann, Scott H

    Cancers

    2021  Volume 13, Issue 24

    Abstract: Despite recent discoveries and therapeutic advances in aggressive myeloid neoplasms, there remains a pressing need for improved therapies. For instance, in acute myeloid leukemia (AML), while most patients achieve a complete remission with conventional ... ...

    Abstract Despite recent discoveries and therapeutic advances in aggressive myeloid neoplasms, there remains a pressing need for improved therapies. For instance, in acute myeloid leukemia (AML), while most patients achieve a complete remission with conventional chemotherapy or the combination of a hypomethylating agent and venetoclax, de novo or acquired drug resistance often presents an insurmountable challenge, especially in older patients. Poly(ADP-ribose) polymerase (PARP) enzymes, PARP1 and PARP2, are involved in detecting DNA damage and repairing it through multiple pathways, including base excision repair, single-strand break repair, and double-strand break repair. In the context of AML, PARP inhibitors (PARPi) could potentially exploit the frequently dysfunctional DNA repair pathways that, similar to deficiencies in homologous recombination in
    Language English
    Publishing date 2021-12-20
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2527080-1
    ISSN 2072-6694
    ISSN 2072-6694
    DOI 10.3390/cancers13246385
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  7. Article ; Online: Eltrombopag directly activates BAK and induces apoptosis.

    Chen, Meng / Hu, Lei / Bao, Xuyuan / Ye, Kaiqin / Li, Yunjian / Zhang, Zhiyong / Kaufmann, Scott H / Xiao, Jun / Dai, Haiming

    Cell death & disease

    2023  Volume 14, Issue 7, Page(s) 394

    Abstract: Small molecule direct BAK activators can potentially be used for the development of anti-cancer drugs or as tools to study BAK activation. The thrombopoietin receptor agonist eltrombopag (Eltro) inhibits BAX activation and BAX-mediated apoptosis. Here we ...

    Abstract Small molecule direct BAK activators can potentially be used for the development of anti-cancer drugs or as tools to study BAK activation. The thrombopoietin receptor agonist eltrombopag (Eltro) inhibits BAX activation and BAX-mediated apoptosis. Here we report that, in contrast to its function as a BAX inhibitor, Eltro directly binds BAK but induces its activation in vitro. Moreover, Eltro induces or sensitizes BAK-dependent cell death in mouse embryonic fibroblasts (MEFs) and Jurkat cells. Chemical shift perturbation analysis by NMR indicates that Eltro binds to the BAK α4/α6/α7 groove to initiate BAK activation. Further molecular docking by HADDOCK suggests that several BAK residues, including R156, F157, and H164, play an important role in the interaction with Eltro. The introduction of an R156E mutation in the BAK α4/α6/α7 groove not only decreases Eltro binding and Eltro-induced BAK activation in vitro but also diminishes Eltro-induced apoptosis. Thus, our data suggest that Eltro directly induces BAK activation and BAK-dependent apoptosis, providing a starting point for the future development of more potent and selective direct BAK activators.
    MeSH term(s) Animals ; Mice ; Molecular Docking Simulation ; bcl-2-Associated X Protein/genetics ; Fibroblasts ; Apoptosis
    Chemical Substances eltrombopag (S56D65XJ9G) ; bcl-2-Associated X Protein
    Language English
    Publishing date 2023-07-01
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2541626-1
    ISSN 2041-4889 ; 2041-4889
    ISSN (online) 2041-4889
    ISSN 2041-4889
    DOI 10.1038/s41419-023-05918-6
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: Manifold medicine: A schema that expands treatment dimensionality.

    Ung, Choong Yong / Weiskittel, Taylor M / Correia, Cristina / Kaufmann, Scott H / Li, Hu

    Drug discovery today

    2021  Volume 27, Issue 1, Page(s) 8–16

    Abstract: Drug discovery currently focuses on identifying new druggable targets and drug repurposing. Here, we illustrate a third domain of drug discovery: the dimensionality of treatment regimens. We formulate a new schema called 'Manifold Medicine', in which ... ...

    Abstract Drug discovery currently focuses on identifying new druggable targets and drug repurposing. Here, we illustrate a third domain of drug discovery: the dimensionality of treatment regimens. We formulate a new schema called 'Manifold Medicine', in which disease states are described by vectorial positions on several body-wide axes. Thus, pathological states are represented by multidimensional 'vectors' that traverse the body-wide axes. We then delineate the manifold nature of drug action to provide a strategy for designing manifold drug cocktails by design using state-of-the-art biomedical and technological innovations. Manifold Medicine offers a roadmap for translating knowledge gained from next-generation technologies into individualized clinical practice.
    MeSH term(s) Disease ; Drug Combinations ; Drug Discovery/methods ; Drug Discovery/trends ; Drug Repositioning/methods ; Drug Repositioning/trends ; Homeostasis/drug effects ; Homeostasis/physiology ; Humans ; Knowledge Bases ; Pharmacology, Clinical/trends ; Precision Medicine/methods ; Precision Medicine/trends ; Systems Theory ; Translational Science, Biomedical/methods
    Chemical Substances Drug Combinations
    Language English
    Publishing date 2021-09-29
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1324988-5
    ISSN 1878-5832 ; 1359-6446
    ISSN (online) 1878-5832
    ISSN 1359-6446
    DOI 10.1016/j.drudis.2021.09.016
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    In stock of ZB MED Cologne/Königswinter

    Zs.A 4725: 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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  9. Article: Uncovering Pharmacological Opportunities for Cancer Stem Cells-A Systems Biology View.

    Correia, Cristina / Weiskittel, Taylor M / Ung, Choong Yong / Villasboas Bisneto, Jose C / Billadeau, Daniel D / Kaufmann, Scott H / Li, Hu

    Frontiers in cell and developmental biology

    2022  Volume 10, Page(s) 752326

    Abstract: Cancer stem cells (CSCs) represent a small fraction of the total cancer cell population, yet they are thought to drive disease propagation, therapy resistance and relapse. Like healthy stem cells, CSCs possess the ability to self-renew and differentiate. ...

    Abstract Cancer stem cells (CSCs) represent a small fraction of the total cancer cell population, yet they are thought to drive disease propagation, therapy resistance and relapse. Like healthy stem cells, CSCs possess the ability to self-renew and differentiate. These stemness phenotypes of CSCs rely on multiple molecular cues, including signaling pathways (for example, WNT, Notch and Hedgehog), cell surface molecules that interact with cellular niche components, and microenvironmental interactions with immune cells. Despite the importance of understanding CSC biology, our knowledge of how neighboring immune and tumor cell populations collectively shape CSC stemness is incomplete. Here, we provide a systems biology perspective on the crucial roles of cellular population identification and dissection of cell regulatory states. By reviewing state-of-the-art single-cell technologies, we show how innovative systems-based analysis enables a deeper understanding of the stemness of the tumor niche and the influence of intratumoral cancer cell and immune cell compositions. We also summarize strategies for refining CSC systems biology, and the potential role of this approach in the development of improved anticancer treatments. Because CSCs are amenable to cellular transitions, we envision how systems pharmacology can become a major engine for discovery of novel targets and drug candidates that can modulate state transitions for tumor cell reprogramming. Our aim is to provide deeper insights into cancer stemness from a systems perspective. We believe this approach has great potential to guide the development of more effective personalized cancer therapies that can prevent CSC-mediated relapse.
    Language English
    Publishing date 2022-03-11
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2737824-X
    ISSN 2296-634X
    ISSN 2296-634X
    DOI 10.3389/fcell.2022.752326
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  10. Article ; Online: A phase I study of pevonedistat, azacitidine, and venetoclax in patients with relapsed/refractory acute myeloid leukemia.

    Murthy, Guru Subramanian Guru / Saliba, Antoine N / Szabo, Aniko / Harrington, Alexandra / Abedin, Sameem / Carlson, Karen / Michaelis, Laura / Runaas, Lyndsey / Baim, Arielle / Hinman, Alex / Maldonado-Schmidt, Sonia / Venkatachalam, Annapoorna / Flatten, Karen S / Peterson, Kevin L / Schneider, Paula A / Litzow, Mark / Kaufmann, Scott H / Atallah, Ehab

    Haematologica

    2024  

    Abstract: Azacitidine/venetoclax is an active regimen in patients with newly diagnosed AML. However, primary or secondary resistance to azacitidine/venetoclax is an area of unmet need and overexpression of MCL-1 is suggested to be a potential resistance mechanism. ...

    Abstract Azacitidine/venetoclax is an active regimen in patients with newly diagnosed AML. However, primary or secondary resistance to azacitidine/venetoclax is an area of unmet need and overexpression of MCL-1 is suggested to be a potential resistance mechanism. Pevonedistat inhibits MCL-1 through activation of NOXA, and pevonedistat/azacitidine has previously shown activity in AML. To assess the tolerability and efficacy of adding pevonedistat to azacitidine/venetoclax in relapsed/refractory AML, we conducted a phase I multicenter openlabel study in 16 adults with relapsed/refractory AML. Patients were treated with azacitidine, venetoclax along with pevonedistat intravenously on days 1, 3 and 5 of each 28-day cycle at 10, 15 or 20 mg/m2 in successive cohorts in the dose escalation phase. The impact of treatment on protein neddylation as well as expression of pro-apoptotic BCL2 family members was assessed. The recommended phase II dose of pevonedistat was 20 mg/m2. Grade 3 or higher adverse events included neutropenia (31%), thrombocytopenia (13%), febrile neutropenia (19%), anemia (19%), hypertension (19%) and sepsis (19%). The overall response rate was 46.7% for the whole cohort including complete remission (CR) in 5 of 7 (71.4%) patients who were naïve to the hypomethylating agent/venetoclax. No measurable residual disease (MRD) was detected in 80.0% of the patients who achieved CR. The median time to best response was 50 (range: 23 - 77) days. Four patients were bridged to allogeneic stem cell transplantation. The combination of azacitidine, venetoclax and pevonedistat is safe and shows encouraging preliminary activity in patients with relapsed/refractory AML. (NCT04172844).
    Language English
    Publishing date 2024-04-04
    Publishing country Italy
    Document type Journal Article
    ZDB-ID 2333-4
    ISSN 1592-8721 ; 0017-6567 ; 0390-6078
    ISSN (online) 1592-8721
    ISSN 0017-6567 ; 0390-6078
    DOI 10.3324/haematol.2024.285014
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Uh III Zs.76: Show issues Location:
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