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  1. Article: Efficacy of Flotetuzumab in Combination with Cytarabine in Patient-Derived Xenograft Models of Pediatric Acute Myeloid Leukemia.

    Barwe, Sonali P / Kisielewski, Anne / Bonvini, Ezio / Muth, John / Davidson-Moncada, Jan / Kolb, Edward Anders / Gopalakrishnapillai, Anilkumar

    Journal of clinical medicine

    2022  Volume 11, Issue 5

    Abstract: Children with acute myeloid leukemia (AML) have a poor prognosis despite the intensification of chemotherapy. Future efforts to improve outcomes should focus on more precise targeting of leukemia cells. CD123, or IL3RA, is expressed on the surface of ... ...

    Abstract Children with acute myeloid leukemia (AML) have a poor prognosis despite the intensification of chemotherapy. Future efforts to improve outcomes should focus on more precise targeting of leukemia cells. CD123, or IL3RA, is expressed on the surface of nearly all pediatric AML samples and is a high-priority target for immunotherapy. The efficacy of an investigational dual-affinity retargeting antibody (DART) molecule (CD123 × CD3; MGD006 or flotetuzumab) was assessed in two distinct patient-derived xenograft (PDX) models of pediatric AML. MGD006 simultaneously binds to CD123 on target cells and CD3 on effector T cells, thereby activating T cells and redirecting them to induce cytotoxicity in target cells. The concurrent treatment of cytarabine and MGD006 was performed to determine the effect of cytarabine on T-cell counts and MGD006 activity. Treatment with MGD006 along with an allogeneic human T-cell infusion to act as effector cells induced durable responses in both PDX models, with CD123 positivity. This effect was sustained in mice treated with a combination of MGD006 and cytarabine in the presence of T cells. MGD006 enhanced T-cell proliferation and decreased the burden of AML blasts in the peripheral blood with or without cytarabine treatment. These data demonstrate the efficacy of MGD006 in prolonging survival in pediatric AML PDX models in the presence of effector T cells and show that the inclusion of cytarabine in the treatment regimen does not interfere with MGD006 activity.
    Language English
    Publishing date 2022-02-28
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2662592-1
    ISSN 2077-0383
    ISSN 2077-0383
    DOI 10.3390/jcm11051333
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  2. Article: Immunotherapeutic Targeting of Mesothelin Positive Pediatric AML Using Bispecific T Cell Engaging Antibodies.

    Gopalakrishnapillai, Anilkumar / Correnti, Colin E / Pilat, Kristina / Lin, Ida / Chan, Man Kid / Bandaranayake, Ashok D / Mehlin, Christopher / Kisielewski, Anne / Hamill, Darcy / Kaeding, Allison J / Meshinchi, Soheil / Olson, James M / Kolb, Edward Anders / Barwe, Sonali P

    Cancers

    2021  Volume 13, Issue 23

    Abstract: Advances in the treatment of pediatric AML have been modest over the past four decades. Despite maximally intensive therapy, approximately 40% of patients will relapse. Novel targeted therapies are needed to improve outcomes. We identified mesothelin ( ... ...

    Abstract Advances in the treatment of pediatric AML have been modest over the past four decades. Despite maximally intensive therapy, approximately 40% of patients will relapse. Novel targeted therapies are needed to improve outcomes. We identified mesothelin (MSLN), a well-validated target overexpressed in some adult malignancies, to be highly expressed on the leukemic cell surface in a subset of pediatric AML patients. The lack of expression on normal bone marrow cells makes MSLN a viable target for immunotherapies such as T-cell engaging bispecific antibodies (BsAbs) that combine two distinct antibody-variable regions into a single molecule targeting a cancer-specific antigen and the T-cell co-receptor CD3. Using antibody single-chain variable region (scFv) sequences derived from amatuximab-recognizing MSLN, and from either blinatumomab or AMG330 targeting CD3, we engineered and expressed two MSLN/CD3-targeting BsAbs: MSLN
    Language English
    Publishing date 2021-11-26
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2527080-1
    ISSN 2072-6694
    ISSN 2072-6694
    DOI 10.3390/cancers13235964
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  3. Article ; Online: A sensitive luminescent assay for the histone methyltransferase NSD1 and other SAM-dependent enzymes.

    Drake, Katherine M / Watson, Venita G / Kisielewski, Anne / Glynn, Rebecca / Napper, Andrew D

    Assay and drug development technologies

    2014  Volume 12, Issue 5, Page(s) 258–271

    Abstract: A major focus of our pediatric cancer research is the discovery of chemical probes to further our understanding of the biology of leukemia harboring fusion proteins arising from chromosomal rearrangements, and to develop novel specifically targeted ... ...

    Abstract A major focus of our pediatric cancer research is the discovery of chemical probes to further our understanding of the biology of leukemia harboring fusion proteins arising from chromosomal rearrangements, and to develop novel specifically targeted therapies. The NUP98-NSD1 fusion protein occurs in a highly aggressive subtype of acute myeloid leukemia after rearrangement of the genes NUP98 and NSD1. The methyltransferase activity of NSD1 is retained in the fusion, and it gives rise to abnormally high levels of methylation at lysine 36 on histone 3, enforcing oncogene activation. Therefore, inhibition of the methyltransferase activity of NUP98-NSD1 may be considered a viable therapeutic strategy. Here, we report the development and validation of a highly sensitive and robust luminescence-based assay for NSD1 and other methyltransferases that use S-adenosylmethionine (SAM) as a methyl donor. The assay quantifies S-adenosylhomocysteine (SAH), which is produced during methyl transfer from SAM. SAH is converted enzymatically to adenosine monophosphate (AMP); in the process, adenosine triphosphate (ATP) is consumed and the amount of ATP remaining is measured using a luminescent assay kit. The assay was validated by pilot high-throughput screening (HTS), dose-response confirmation of hits, and elimination of artifacts through counterscreening against SAH detection in the absence of NSD1. The known methyltransferase inhibitor suramin was identified, and profiled for selectivity against the histone methyltransferases EZH2, SETD7, and PRMT1. HTS using the luminescent NSD1 assay described here has the potential to deliver selective NSD1 inhibitors that may serve as leads in the development of targeted therapies for NUP98-NSD1-driven leukemias.
    MeSH term(s) Dose-Response Relationship, Drug ; Enzyme Assays/methods ; Enzyme Inhibitors/analysis ; Enzyme Inhibitors/chemistry ; Enzyme Inhibitors/pharmacology ; High-Throughput Screening Assays ; Histone Methyltransferases ; Histone-Lysine N-Methyltransferase ; Humans ; Intracellular Signaling Peptides and Proteins/antagonists & inhibitors ; Intracellular Signaling Peptides and Proteins/metabolism ; Luminescent Measurements/methods ; Methyltransferases/antagonists & inhibitors ; Methyltransferases/metabolism ; Nuclear Proteins/antagonists & inhibitors ; Nuclear Proteins/metabolism ; S-Adenosylmethionine/metabolism ; Structure-Activity Relationship
    Chemical Substances Enzyme Inhibitors ; Intracellular Signaling Peptides and Proteins ; Nuclear Proteins ; S-Adenosylmethionine (7LP2MPO46S) ; Histone Methyltransferases (EC 2.1.1.-) ; Methyltransferases (EC 2.1.1.-) ; Histone-Lysine N-Methyltransferase (EC 2.1.1.43) ; NSD1 protein, human (EC 2.1.1.43)
    Language English
    Publishing date 2014-06-13
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Validation Study
    ISSN 1557-8127
    ISSN (online) 1557-8127
    DOI 10.1089/adt.2014.583
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    2005 A 2339: Show issues

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  4. Article ; Online: A transcriptome-wide screen for mRNAs enriched in fetal Leydig cells: CRHR1 agonism stimulates rat and mouse fetal testis steroidogenesis.

    McDowell, Erin N / Kisielewski, Anne E / Pike, Jack W / Franco, Heather L / Yao, Humphrey H-C / Johnson, Kamin J

    PloS one

    2012  Volume 7, Issue 10, Page(s) e47359

    Abstract: Fetal testis steroidogenesis plays an important role in the reproductive development of the male fetus. While regulators of certain aspects of steroidogenesis are known, the initial driver of steroidogenesis in the human and rodent fetal testis is ... ...

    Abstract Fetal testis steroidogenesis plays an important role in the reproductive development of the male fetus. While regulators of certain aspects of steroidogenesis are known, the initial driver of steroidogenesis in the human and rodent fetal testis is unclear. Through comparative analysis of rodent fetal testis microarray datasets, 54 candidate fetal Leydig cell-specific genes were identified. Fetal mouse testis interstitial expression of a subset of these genes with unknown expression (Crhr1, Gramd1b, Itih5, Vgll3, and Vsnl1) was verified by whole-mount in situ hybridization. Among the candidate fetal Leydig cell-specific factors, three receptors (CRHR1, PRLR, and PROKR2) were tested for a steroidogenic function using ex vivo fetal testes treated with receptor agonists (CRH, PRL, and PROK2). While PRL and PROK2 had no effect, CRH, at low (approximately 1 to 10) nM concentration, increased expression of the steroidogenic genes Cyp11a1, Cyp17a1, Scarb1, and Star in GD15 mouse and GD17 rat testes, and in conjunction, testosterone production was increased. Exposure of GD15 fetal mouse testis to a specific CRHR1 antagonist blunted the CRH-induced steroidogenic gene expression and testosterone responses. Similar to ex vivo rodent fetal testes, ≥ 10 nM CRH exposure of MA-10 Leydig cells increased steroidogenic pathway mRNA and progesterone levels, showing CRH can enhance steroidogenesis by directly targeting Leydig cells. Crh mRNA expression was observed in rodent fetal hypothalamus, and CRH peptide was detected in rodent amniotic fluid. Together, these data provide a resource for discovering factors controlling fetal Leydig cell biology and suggest that CRHR1 activation by CRH stimulates rat and mouse fetal Leydig cell steroidogenesis in vivo.
    MeSH term(s) Amniotic Fluid/metabolism ; Animals ; C-Reactive Protein/metabolism ; Gastrointestinal Hormones/metabolism ; Gene Expression Regulation, Developmental ; Genomics ; Immunohistochemistry/methods ; Leydig Cells/metabolism ; Male ; Mice ; Neuropeptides/metabolism ; Oligonucleotide Array Sequence Analysis ; Prolactin/biosynthesis ; RNA, Messenger/metabolism ; Rats ; Rats, Sprague-Dawley ; Receptors, Corticotropin-Releasing Hormone/agonists ; Receptors, Corticotropin-Releasing Hormone/physiology ; Steroids/metabolism ; Testis/embryology ; Testosterone/metabolism ; Time Factors ; Urocortins/metabolism
    Chemical Substances Gastrointestinal Hormones ; Neuropeptides ; Prok2 protein, mouse ; RNA, Messenger ; Receptors, Corticotropin-Releasing Hormone ; Steroids ; Ucn1 protein, mouse ; Urocortins ; Testosterone (3XMK78S47O) ; CRF receptor type 1 (5CLY6W2H1M) ; Prolactin (9002-62-4) ; C-Reactive Protein (9007-41-4)
    Language English
    Publishing date 2012-10-25
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't
    ISSN 1932-6203
    ISSN (online) 1932-6203
    DOI 10.1371/journal.pone.0047359
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  5. Article ; Online: Manipulation of gene expression by an ecdysone-inducible gene switch in tumor xenografts

    Gulding Kathryn M / Kisielewski Anne / Karns Larry R / Theodorescu Dan

    BMC Biotechnology, Vol 1, Iss 1, p

    2001  Volume 11

    Abstract: abstract Background Rapid, robust and reversible induction of transgene expression would significantly facilitate cancer gene therapy as well as allow the in vivo functional study of newly discovered genes in tumor formation and progression. The ... ...

    Abstract abstract Background Rapid, robust and reversible induction of transgene expression would significantly facilitate cancer gene therapy as well as allow the in vivo functional study of newly discovered genes in tumor formation and progression. The popularity of the ecdysone inducible gene switch system has led us to investigate whether such a system can successfully regulate gene expression in a syngeneic tumor system in vivo. Results MBT-2 and Panc02 carcinoma cells were transfected with components of a modification of the ecdysone switch system driving firefly luciferase (F-Luc). In vitro luciferase expression ± ecdysone analog GS-E indicated a robust induction with minimal baseline activity and complete decay after 24 hours without drug. In vitro selection of MBT-2 transfected cell clones which had complete absence of F-Luc expression in the absence of stimulation but which expressed this gene at high levels in response to GS-E were chosen for in vivo evaluation. Tumors from engineered MBT-2 cells were grown to 5 mm in diameter prior to GS-E administration, animals euthanized and tumors removed at 6, 12 and 24 hours after GS-E administration and assayed for F-Luc activity. GS-E resulted in a maximal induction of F-Luc activity at 6 hours in tumor tissue with almost complete reversion to control levels by 12 hours. Conclusions This study is the first demonstration that robust and reversible transgene expression in tumors is feasible using the ecdysone system, allowing future rapid in vivo functional characterization of gene function or gene therapy applications.
    Keywords Ecdysone ; Gene Expression Regulation. Ligands ; Mice ; Transcription Factors ; Tumor Cells ; Biotechnology ; TP248.13-248.65 ; Chemical technology ; TP1-1185 ; Technology ; T ; DOAJ:Biotechnology ; DOAJ:Life Sciences ; DOAJ:Biology and Life Sciences
    Language English
    Publishing date 2001-12-01T00:00:00Z
    Publisher BioMed Central
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article: Design and synthesis of compounds that extend yeast replicative lifespan.

    Yang, Hongying / Baur, Joseph A / Chen, Allen / Miller, Christine / Adams, Jeffrey K / Kisielewski, Anne / Howitz, Konrad T / Zipkin, Robert E / Sinclair, David A

    Aging cell

    2007  Volume 6, Issue 1, Page(s) 35–43

    Abstract: This past decade has seen the identification of numerous conserved genes that extend lifespan in diverse species, yet the number of compounds that extend lifespan is relatively small. A class of compounds called STACs, which were identified as activators ...

    Abstract This past decade has seen the identification of numerous conserved genes that extend lifespan in diverse species, yet the number of compounds that extend lifespan is relatively small. A class of compounds called STACs, which were identified as activators of Sir2/SIRT1 NAD+-dependent deacetylases, extend the lifespans of multiple species in a Sir2-dependent manner and can delay the onset of age-related diseases such as cancer, diabetes and neurodegeneration in model organisms. Plant-derived STACs such as fisetin and resveratrol have several liabilities, including poor stability and relatively low potency as SIRT1 activators. To develop improved STACs, stilbene derivatives with modifications at the 4' position of the B ring were synthesized using a Horner-Emmons-based synthetic route or by hydrolyzing deoxyrhapontin. Here, we describe synthetic STACs with lower toxicity toward human cells, and higher potency with respect to SIRT1 activation and lifespan extension in Saccharomyces cerevisiae. These studies show that it is possible to improve upon naturally occurring STACs based on a number of criteria including lifespan extension.
    MeSH term(s) Cell Line ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Cellular Senescence/drug effects ; Cellular Senescence/physiology ; Dose-Response Relationship, Drug ; Drug Design ; Enzyme Activation/drug effects ; Enzyme Activation/physiology ; Flavonoids/pharmacology ; Humans ; Molecular Structure ; Saccharomyces cerevisiae/drug effects ; Saccharomyces cerevisiae/metabolism ; Sirtuin 1 ; Sirtuins/drug effects ; Sirtuins/metabolism ; Stilbenes/chemical synthesis ; Stilbenes/pharmacology ; Stilbenes/toxicity
    Chemical Substances Flavonoids ; Stilbenes ; SIRT1 protein, human (EC 3.5.1.-) ; Sirtuin 1 (EC 3.5.1.-) ; Sirtuins (EC 3.5.1.-) ; fisetin (OO2ABO9578) ; resveratrol (Q369O8926L)
    Language English
    Publishing date 2007-02
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2113083-8
    ISSN 1474-9726 ; 1474-9718
    ISSN (online) 1474-9726
    ISSN 1474-9718
    DOI 10.1111/j.1474-9726.2006.00259.x
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    In stock of ZB MED Cologne/Königswinter

    Zs.A 6581: Show issues Location:
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  7. Article ; Online: Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan.

    Howitz, Konrad T / Bitterman, Kevin J / Cohen, Haim Y / Lamming, Dudley W / Lavu, Siva / Wood, Jason G / Zipkin, Robert E / Chung, Phuong / Kisielewski, Anne / Zhang, Li-Li / Scherer, Brandy / Sinclair, David A

    Nature

    2003  Volume 425, Issue 6954, Page(s) 191–196

    Abstract: In diverse organisms, calorie restriction slows the pace of ageing and increases maximum lifespan. In the budding yeast Saccharomyces cerevisiae, calorie restriction extends lifespan by increasing the activity of Sir2 (ref. 1), a member of the conserved ... ...

    Abstract In diverse organisms, calorie restriction slows the pace of ageing and increases maximum lifespan. In the budding yeast Saccharomyces cerevisiae, calorie restriction extends lifespan by increasing the activity of Sir2 (ref. 1), a member of the conserved sirtuin family of NAD(+)-dependent protein deacetylases. Included in this family are SIR-2.1, a Caenorhabditis elegans enzyme that regulates lifespan, and SIRT1, a human deacetylase that promotes cell survival by negatively regulating the p53 tumour suppressor. Here we report the discovery of three classes of small molecules that activate sirtuins. We show that the potent activator resveratrol, a polyphenol found in red wine, lowers the Michaelis constant of SIRT1 for both the acetylated substrate and NAD(+), and increases cell survival by stimulating SIRT1-dependent deacetylation of p53. In yeast, resveratrol mimics calorie restriction by stimulating Sir2, increasing DNA stability and extending lifespan by 70%. We discuss possible evolutionary origins of this phenomenon and suggest new lines of research into the therapeutic use of sirtuin activators.
    MeSH term(s) Acetylation/drug effects ; Caloric Restriction ; Catalysis/drug effects ; Cell Line ; Cell Survival/drug effects ; Cellular Senescence/drug effects ; Flavonoids ; Histone Deacetylases/genetics ; Histone Deacetylases/metabolism ; Humans ; Kinetics ; Longevity/drug effects ; Phenols/pharmacology ; Polymers/pharmacology ; Polyphenols ; Recombination, Genetic/drug effects ; Saccharomyces cerevisiae/cytology ; Saccharomyces cerevisiae/drug effects ; Saccharomyces cerevisiae/genetics ; Saccharomyces cerevisiae/metabolism ; Silent Information Regulator Proteins, Saccharomyces cerevisiae/agonists ; Silent Information Regulator Proteins, Saccharomyces cerevisiae/genetics ; Silent Information Regulator Proteins, Saccharomyces cerevisiae/metabolism ; Sirtuin 1 ; Sirtuin 2 ; Sirtuins/agonists ; Sirtuins/genetics ; Sirtuins/metabolism ; Stilbenes/pharmacology ; Tumor Suppressor Protein p53/metabolism ; Wine
    Chemical Substances Flavonoids ; Phenols ; Polymers ; Polyphenols ; Silent Information Regulator Proteins, Saccharomyces cerevisiae ; Stilbenes ; Tumor Suppressor Protein p53 ; SIR2 protein, S cerevisiae (EC 3.5.1.-) ; SIRT1 protein, human (EC 3.5.1.-) ; Sirtuin 1 (EC 3.5.1.-) ; Sirtuin 2 (EC 3.5.1.-) ; Sirtuins (EC 3.5.1.-) ; Histone Deacetylases (EC 3.5.1.98) ; resveratrol (Q369O8926L)
    Language English
    Publishing date 2003-09-11
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, U.S. Gov't, P.H.S.
    ZDB-ID 120714-3
    ISSN 1476-4687 ; 0028-0836
    ISSN (online) 1476-4687
    ISSN 0028-0836
    DOI 10.1038/nature01960
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    In stock of ZB MED Cologne/Königswinter

    Zs.A 26: Show issues Location:
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