1,724,557 research outputs found
NS H 7738, hibrid suncokreta (Ukrajina)
No full textNS H 7738, hibrid suncokreta, priznat od strane Ministarstva za poljoprivredu Ukrajine (Міністерство аграрної політики та продовольства України), rešenje Državne komisije za zaštitu biljnih sorti (Державна служба з охорони прав на сорти рослин) br. 17039146 od 11.02.2020. godine, Ukrajina
NUC-7738 regulates β-catenin signalling resulting in reduced proliferation and self-renewal of AML cells
Full text linkFunding: This study was supported by research funding from NuCana plc to all authors.Acute myeloid leukemia (AML) stem cells are required for the initiation and maintenance of the disease. Activation of the Wnt/β-catenin pathway is required for the survival and development of AML leukaemia stem cells (LSCs) and therefore, targeting β-catenin is a potential therapeutic strategy. NUC-7738, a phosphoramidate transformation of 3’-deoxyadenosine (3’-dA) monophosphate, is specifically designed to generate the active anti-cancer metabolite 3’-deoxyadenosine triphosphate (3’-dATP) intracellularly, bypassing key limitations of breakdown, transport, and activation. NUC-7738 is currently in a Phase I/II clinical study for the treatment of patients with advanced solid tumors. Protein expression and immunophenotypic profiling revealed that NUC-7738 caused apoptosis in AML cell lines through reducing PI3K-p110α, phosphorylated Akt (Ser473) and phosphorylated GSK3β (Ser9) resulting in reduced β-catenin, c-Myc and CD44 expression. NUC-7738 reduced β-catenin nuclear expression in AML cells. NUC-7738 also decreased the percentage of CD34+ CD38- CD123+ (LSC-like cells) from 81% to 47% and reduced the total number and size of leukemic colonies. These results indicate that therapeutic targeting of the PI3K/Akt/GSK3β axis can inhibit β-catenin signalling, resulting in reduced clonogenicity and eventual apoptosis of AML cells.Peer reviewe
NUC-7738 induces apoptosis in AML cell lines.
No full textOCI-AML3 and U937 cells were treated with NUC-7738 at 5, 10 and 20 μM for 48 hrs and apoptosis was determined by Annexin-V DAPI staining. (A) dot plots generated during flow cytometry analysis highlighting the percentage of live (LL), early apoptotic (LR), late apoptotic (UR) and dead (UL) cells. (B) Bar graphs highlight the proportion of cells which are viable, in early apoptosis or in late apoptosis as determined by Annexin-V / DAPI staining, and analysis by flow cytometry. The percentages shown indicate the proportion of total events within each of the respective categories as gated on the flow cytometry plots. Gating strategy highlighted in S1 Fig in S1 File. Each bar represents the mean percentage from three independent experiments with error bars indicating SD showing NUC-7738 caused a reduction in viable cells and an increase in early and late apoptotic cells in all cells examined. NUC-7738 did not induce apoptosis in the KG1a cell line (S20 Fig in S1 File).</p
PI3K/Akt/MAPK signaling is involved in NUC-7738 mediated suppression of β-catenin.
No full text(A) HL-60, (B) OCI-AML3 were treated with 10 and 20 μM NUC-7738, whereas (C) U937 cells were only treated with 10 μM for 48 hrs. Expression level of PI3K-p110α, phosphorylated Akt (Ser473) and phosphorylated GSK3β (Ser9) was determined by Western blot analysis and bands normalised to total protein. In each cell line tested there was >40% reduction in the protein levels of phosphorylated Akt (Ser473) and phosphorylated GSK3β (Ser9), following 48 hrs NUC-7738 treatment.</p
Registration of Three Leafminer‐Resistant Chickpea Germplasm Lines: ILC 3800, ILC 5901, and ILC 7738
No full textRegistration of Three Leafminer‐Resistant Chickpea Germplasm Lines: ILC 3800, ILC 5901, and ILC 7738
NUC-7738 inhibits β-catenin and its target genes c-Myc and CD44.
No full textOCI-AML3, HL-60 and KG1a cells were treated with NUC-7738 at 10 and 20 μM for 48 hrs, U937 cells were only treated with 10 μM. β-catenin (A), c-Myc (B) and CD44 (C) protein levels were determined by Western blot analysis and bands were normalised to total protein. Protein levels of β-catenin, c-Myc and CD44 were all reduced in a dose-dependent manner in all tested cell lines following 48 hrs NUC-7738 treatment. (D) β-catenin was localised using immunofluorescence, highlighting the non-nuclear localisation of β-catenin (white arrow) following 48 hrs treatment with NUC-7738 in OCI-AML3 and the reduction of total β-catenin. These data are from three independent experiments. Each bar denotes mean ± SD * P<0.05, ** P<0.01, **** P< 0.001.</p
Abstract C032: NUC-7738 in combination with pembrolizumab in patients with metastatic melanoma: Phase 2 results from the NuTide:701 study
No full textBackground: 3’-deoxyadenosine (3’-dA) is a natural nucleoside analogue that demonstrated potent anti-cancer activity in vitro but was not successfully developed in the clinic due to rapid breakdown and limited activation to the anti-cancer metabolite (3’-dATP). NUC-7738 is a phosphoramidate modification of 3’-dA designed to overcome these shortcomings and generate higher levels of 3’-dATP. Primarily, 3’-dATP disrupts RNA polyadenylation and can cause metabolic stress, blockade of cell division and apoptosis. Secreted forms of PD-L1, associated with resistance to PD-1 inhibitors, are partially controlled by alternative polyadenylation and were found to be reduced by NUC-7738 in vitro and in some patient (pt) samples. NuTide:701 is a two-part, Phase 1/2 clinical study designed to establish the RP2D of NUC-7738 monotherapy and to investigate NUC-7738 at the RP2D in combination with pembrolizumab. NUC-7738 monotherapy has shown a favourable safety profile and anti-tumour activity (prolonged SD and tumour reductions). Here we focus on the Phase 2 NUC-7738 + pembrolizumab part of the study.Methods: Pts with advanced/metastatic cutaneous melanoma who had progressed on 1- 2 prior lines, one of which may have contained immunotherapy, are included in the ongoing NUC-7738 + pembrolizumab cohort and receive NUC-7738 1125 mg/m2 Q1W (with option to escalate to 1350 mg/m2 beyond C2D8) and pembrolizumab 200 mg/m2 Q3W until progression. In pts with accessible disease, biopsies were taken prior to and 28 days after initiation of treatment to assess tumour levels of NUC-7738 and its metabolites and evaluate changes in the tumour microenvironment.Results: At the time of data cut-off, 4 pts with cutaneous melanoma have received NUC-7738 + pembrolizumab. To date, 1 pt experienced reversable Grade 4 transaminitis, related to pembrolizumab, and 2 pts experienced Grade 3 abdominal pain, diarrhoea and fatigue. At the time of writing, all 4 remain on treatment, 1 pt has SD and 8 additional pts are being recruited.Conclusions: NUC-7738 has a favourable toxicity profile as monotherapy and has been well-tolerated to date in combination with pembrolizumab. Available clinical and translational data for all pts treated with NUC-7738 + pembrolizumab will be presented. Clinical trial information: NCT03428958Citation Format: Sarah P Blagden, Stefan N Symeonides, Aglaia Skolariki, Noor Md Haris, Zhuang Boh, In Hwa Um, Mustafa Elshani, Alison L Dickson, Ying Zhang, David J Harrison, Fiona G McKissock, Elisabeth Oelmann, Jeffrey D Bloss, Natalie Cook, TR Jeffry Evans, E. Ruth Plummer. NUC-7738 in combination with pembrolizumab in patients with metastatic melanoma: Phase 2 results from the NuTide:701 study [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C032
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
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