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  1. Article ; Online: A CDC7 inhibitor sensitizes DNA-damaging chemotherapies by suppressing homologous recombination repair to delay DNA damage recovery.

    Iwai, Kenichi / Nambu, Tadahiro / Kashima, Yukie / Yu, Jie / Eng, Kurt / Miyamoto, Kazumasa / Kakoi, Kazuyo / Gotou, Masamitsu / Takeuchi, Toshiyuki / Kogame, Akifumi / Sappal, Jessica / Murai, Saomi / Haeno, Hiroshi / Kageyama, Shun-Ichiro / Kurasawa, Osamu / Niu, Huifeng / Kannan, Karuppiah / Ohashi, Akihiro

    Science advances

    2021  Volume 7, Issue 21

    Abstract: Cell division cycle 7 (CDC7), a serine/threonine kinase, plays important roles in DNA replication. We developed a highly specific CDC7 inhibitor, TAK-931, as a clinical cancer therapeutic agent. This study aimed to identify the potential combination ... ...

    Abstract Cell division cycle 7 (CDC7), a serine/threonine kinase, plays important roles in DNA replication. We developed a highly specific CDC7 inhibitor, TAK-931, as a clinical cancer therapeutic agent. This study aimed to identify the potential combination partners of TAK-931 for guiding its clinical development strategies. Unbiased high-throughput chemical screening revealed that the highest synergistic antiproliferative effects observed were the combinations of DNA-damaging agents with TAK-931. Functional phosphoproteomic analysis demonstrated that TAK-931 suppressed homologous recombination repair activity, delayed recovery from double-strand breaks, and led to accumulation of DNA damages in the combination. Whole-genome small interfering RNA library screening identified sensitivity-modulating molecules, which propose the experimentally predicted target cancer types for the combination, including pancreatic, esophageal, ovarian, and breast cancers. The efficacy of combination therapy in these cancer types was preclinically confirmed in the corresponding primary-derived xenograft models. Thus, our findings would be helpful to guide the future clinical strategies for TAK-931.
    MeSH term(s) Cell Cycle Proteins/metabolism ; Cell Line, Tumor ; DNA ; DNA Damage ; Humans ; Neoplasms/drug therapy ; Neoplasms/genetics ; Protein Serine-Threonine Kinases ; Recombinational DNA Repair
    Chemical Substances Cell Cycle Proteins ; DNA (9007-49-2) ; CDC7 protein, human (EC 2.7.1.-) ; Protein Serine-Threonine Kinases (EC 2.7.11.1)
    Language English
    Publishing date 2021-05-21
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2810933-8
    ISSN 2375-2548 ; 2375-2548
    ISSN (online) 2375-2548
    ISSN 2375-2548
    DOI 10.1126/sciadv.abf0197
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: RNAi screening in primary human hepatocytes of genes implicated in genome-wide association studies for roles in type 2 diabetes identifies roles for CAMK1D and CDKAL1, among others, in hepatic glucose regulation.

    Haney, Steven / Zhao, Juan / Tiwari, Shiwani / Eng, Kurt / Guey, Lin T / Tien, Eric

    PloS one

    2013  Volume 8, Issue 6, Page(s) e64946

    Abstract: Genome-wide association (GWA) studies have described a large number of new candidate genes that contribute to of Type 2 Diabetes (T2D). In some cases, small clusters of genes are implicated, rather than a single gene, and in all cases, the genetic ... ...

    Abstract Genome-wide association (GWA) studies have described a large number of new candidate genes that contribute to of Type 2 Diabetes (T2D). In some cases, small clusters of genes are implicated, rather than a single gene, and in all cases, the genetic contribution is not defined through the effects on a specific organ, such as the pancreas or liver. There is a significant need to develop and use human cell-based models to examine the effects these genes may have on glucose regulation. We describe the development of a primary human hepatocyte model that adjusts glucose disposition according to hormonal signals. This model was used to determine whether candidate genes identified in GWA studies regulate hepatic glucose disposition through siRNAs corresponding to the list of identified genes. We find that several genes affect the storage of glucose as glycogen (glycolytic response) and/or affect the utilization of pyruvate, the critical step in gluconeogenesis. Of the genes that affect both of these processes, CAMK1D, TSPAN8 and KIF11 affect the localization of a mediator of both gluconeogenesis and glycolysis regulation, CRTC2, to the nucleus in response to glucagon. In addition, the gene CDKAL1 was observed to affect glycogen storage, and molecular experiments using mutant forms of CDK5, a putative target of CDKAL1, in HepG2 cells show that this is mediated by coordinate regulation of CDK5 and PKA on MEK, which ultimately regulates the phosphorylation of ribosomal protein S6, a critical step in the insulin signaling pathway.
    MeSH term(s) Calcium-Calmodulin-Dependent Protein Kinase Type 1/genetics ; Cyclic AMP-Dependent Protein Kinases/metabolism ; Cyclin-Dependent Kinase 5/genetics ; Cyclin-Dependent Kinase 5/metabolism ; Diabetes Mellitus, Type 2/genetics ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Gene Knockdown Techniques ; Genome, Human ; Genome-Wide Association Study ; Glucagon/physiology ; Glucose/metabolism ; Glycogen/metabolism ; Hep G2 Cells ; Hepatocytes/metabolism ; Homeostasis ; Humans ; Intracellular Signaling Peptides and Proteins/genetics ; Intracellular Signaling Peptides and Proteins/metabolism ; Phosphoenolpyruvate Carboxykinase (GTP)/genetics ; Phosphoenolpyruvate Carboxykinase (GTP)/metabolism ; Phosphorylation ; Polymorphism, Single Nucleotide ; Primary Cell Culture ; Protein Processing, Post-Translational ; Protein Transport ; Pyruvic Acid/metabolism ; RNA Interference ; RNA, Small Interfering/genetics ; Ribosomal Protein S6 Kinases/metabolism ; Signal Transduction ; Transcription Factors/metabolism ; tRNA Methyltransferases
    Chemical Substances CRTC2 protein, human ; Intracellular Signaling Peptides and Proteins ; RNA, Small Interfering ; Transcription Factors ; Pyruvic Acid (8558G7RUTR) ; Glycogen (9005-79-2) ; Glucagon (9007-92-5) ; tRNA Methyltransferases (EC 2.1.1.-) ; Cyclin-Dependent Kinase 5 (EC 2.7.11.1) ; Ribosomal Protein S6 Kinases (EC 2.7.11.1) ; Cyclic AMP-Dependent Protein Kinases (EC 2.7.11.11) ; CAMK1D protein, human (EC 2.7.11.17) ; Calcium-Calmodulin-Dependent Protein Kinase Type 1 (EC 2.7.11.17) ; CDK5 protein, human (EC 2.7.11.22) ; Extracellular Signal-Regulated MAP Kinases (EC 2.7.11.24) ; CDKAL1 protein, human (EC 2.8.4.5) ; PCK1 protein, human (EC 4.1.1.32) ; Phosphoenolpyruvate Carboxykinase (GTP) (EC 4.1.1.32) ; Glucose (IY9XDZ35W2)
    Language English
    Publishing date 2013-06-20
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2267670-3
    ISSN 1932-6203 ; 1932-6203
    ISSN (online) 1932-6203
    ISSN 1932-6203
    DOI 10.1371/journal.pone.0064946
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Preclinical Antitumor Activity and Biodistribution of a Novel Anti-GCC Antibody-Drug Conjugate in Patient-derived Xenografts.

    Abu-Yousif, Adnan O / Cvet, Donna / Gallery, Melissa / Bannerman, Bret M / Ganno, Michelle L / Smith, Michael D / Lai, Katharine C / Keating, Thomas A / Stringer, Bradley / Kamali, Afrand / Eng, Kurt / Koseoglu, Secil / Zhu, Andy / Xia, Cindy Q / Landen, Melissa Saylor / Borland, Maria / Robertson, Robbie / Bolleddula, Jayaprakasam / Qian, Mark G /
    Fretland, Jennifer / Veiby, O Petter

    Molecular cancer therapeutics

    2020  Volume 19, Issue 10, Page(s) 2079–2088

    Abstract: Guanylyl cyclase C (GCC) is a unique therapeutic target with expression restricted to the apical side of epithelial cell tight junctions thought to be only accessible by intravenously administered agents on malignant tissues where GCC expression is ... ...

    Abstract Guanylyl cyclase C (GCC) is a unique therapeutic target with expression restricted to the apical side of epithelial cell tight junctions thought to be only accessible by intravenously administered agents on malignant tissues where GCC expression is aberrant. In this study, we sought to evaluate the therapeutic potential of a second-generation investigational antibody-dug conjugate (ADC), TAK-164, comprised of a human anti-GCC mAb conjugated via a peptide linker to the highly cytotoxic DNA alkylator, DGN549. The
    MeSH term(s) Animals ; Female ; HEK293 Cells ; Humans ; Immunoconjugates/pharmacology ; Immunoconjugates/therapeutic use ; Mice ; Mice, Nude ; Tissue Distribution ; Xenograft Model Antitumor Assays
    Chemical Substances Immunoconjugates
    Language English
    Publishing date 2020-08-11
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2063563-1
    ISSN 1538-8514 ; 1535-7163
    ISSN (online) 1538-8514
    ISSN 1535-7163
    DOI 10.1158/1535-7163.MCT-19-1102
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 5750: 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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  4. Article: Use of a monoclonal antibody specific for activated endothelial cells to quantitate angiogenesis in vivo in zebrafish after drug treatment.

    Seng, Wen Lin / Eng, Kurt / Lee, Jenny / McGrath, Patricia

    Angiogenesis

    2004  Volume 7, Issue 3, Page(s) 243–253

    Abstract: We have recently generated a monoclonal antibody (mAb), Phy-V002, which specifically labels activated vascular endothelial cells (EC) in zebrafish. Here, we show that this mAb labels activated EC in newly formed vessels in vivo without staining mature ... ...

    Abstract We have recently generated a monoclonal antibody (mAb), Phy-V002, which specifically labels activated vascular endothelial cells (EC) in zebrafish. Here, we show that this mAb labels activated EC in newly formed vessels in vivo without staining mature vessels or other tissues. Using this mAb, drug effects on in vivo EC migration and vessel formation were visually assessed by whole-mount immunochemical staining in the transparent embryo. In addition, we have developed a quantitative microplate-based ELISA that measures EC proliferation in vivo after drug treatment. We have validated the quantitative in vivo ELISA using several antiangiogenic small molecules with different mechanisms of action which were added directly to the fish water. Some of these drugs, including: 2-methoxyestradiol, flavopiridol, paclitaxel, and genistein, are currently in clinical trials. We also injected large molecule drugs, including 3TSR and TSR2+KRFK, recombinant human antiangiogenic peptides of thrombospondin-1, a natural protein. To demonstrate that proangiogenic effects can also be assessed in zebrafish, we assessed effects of penicillamine and simvastatin, two proangiogenic compounds shown to stimulate vessel formation in rodents. Using whole-mount immunochemical staining with Phy-V002, inhibition of EC migration and inhibition or stimulation of vessel formation were visually observed for each compound. Next, using the quantitative in vivo angiogenesis ELISA, we generated dose-response curves for each compound. Compared to conventional assays, advantages of using zebrafish to assess drug effects on angiogenesis include: (1) a short assay time; (2) easy animal maintenance; (3) use of small quantities of drug; (4) single dosing; (5) a quantitative assay format; and (6) use of statistically significant number of animals per test.
    MeSH term(s) Angiogenesis Inducing Agents/pharmacology ; Angiogenesis Inhibitors/pharmacology ; Animals ; Antibodies, Monoclonal/immunology ; Antibodies, Monoclonal/pharmacology ; Blood Vessels/drug effects ; Blood Vessels/immunology ; Cell Movement/drug effects ; Cell Proliferation/drug effects ; Dose-Response Relationship, Drug ; Drug Evaluation, Preclinical/methods ; Embryo, Nonmammalian/immunology ; Endothelial Cells/drug effects ; Endothelial Cells/immunology ; Endothelium, Vascular/cytology ; Endothelium, Vascular/drug effects ; Endothelium, Vascular/immunology ; Enzyme-Linked Immunosorbent Assay ; Neovascularization, Physiologic/drug effects ; Penicillamine/pharmacology ; Simvastatin/pharmacology ; Staining and Labeling/methods ; Zebrafish/embryology ; Zebrafish/immunology
    Chemical Substances Angiogenesis Inducing Agents ; Angiogenesis Inhibitors ; Antibodies, Monoclonal ; Simvastatin (AGG2FN16EV) ; Penicillamine (GNN1DV99GX)
    Language English
    Publishing date 2004
    Publishing country Germany
    Document type Journal Article ; Research Support, U.S. Gov't, P.H.S.
    ZDB-ID 1484717-6
    ISSN 0969-6970
    ISSN 0969-6970
    DOI 10.1007/s10456-004-4181-7
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    In stock of ZB MED Cologne/Königswinter

    Zs.A 5094: 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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  5. Article: A bilayer small diameter

    Hoganson, David M / Finkelstein, Eric B / Owens, Gwen E / Hsiao, James C / Eng, Kurt Y / Kulig, Katherine M / Kim, Ernest S / Kniazeva, Tatiana / Pomerantseva, Irina / Neville, Craig M / Turk, James R / Fermini, Bernard / Borenstein, Jeffrey T / Vacanti, Joseph P

    Biomicrofluidics

    2016  Volume 10, Issue 5, Page(s) 54116

    Abstract: In pre-clinical safety studies, drug-induced vascular injury (DIVI) is defined as an adverse response to a drug characterized by degenerative and hyperplastic changes of endothelial cells and vascular smooth muscle cells. Inflammation may also be seen, ... ...

    Abstract In pre-clinical safety studies, drug-induced vascular injury (DIVI) is defined as an adverse response to a drug characterized by degenerative and hyperplastic changes of endothelial cells and vascular smooth muscle cells. Inflammation may also be seen, along with extravasation of red blood cells into the smooth muscle layer (i.e., hemorrhage). Drugs that cause DIVI are often discontinued from development after considerable cost has occurred. An
    Language English
    Publishing date 2016-10-12
    Publishing country United States
    Document type Journal Article
    ISSN 1932-1058
    ISSN 1932-1058
    DOI 10.1063/1.4964814
    Database MEDical Literature Analysis and Retrieval System OnLINE

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