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https://www.readbyqxmd.com/read/29107421/discovery-of-novel-pyrrolo-pyridine-pyrimidine-derivatives-bearing-pyridazinone-moiety-as-c-met-kinase-inhibitors
#1
Lin Xiao Wang, Xiaobo Liu, Shan Xu, Qidong Tang, Yongli Duan, Zhen Xiao, Jia Zhi, Liwen Jiang, Pengwu Zheng, Wufu Zhu
In continue to our previous research, eight series of pyrrolo[2,3-b]pyridine and pyrrolo[2,3-d]pyrimidine derivatives bearing pyridazinone moiety were designed, synthesized, and the in vitro antitumor activity was evaluated against four cancer cell lines (A549, HepG2, MCF-7 and PC-3). Some selected compounds (22f, 22g, 26c and 26e) were evaluated for the activity against c-Met kinase, and according to the results of kinase inhibitory activity, the compound 22g was further evaluated for other four tyrosine kinases (Flt-3, VEGFR-2, c-Kit and EGFR) to test the enzyme-based selectivity...
December 1, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29042609/structural-analysis-of-pim1-kinase-complexes-with-atp-competitive-inhibitors
#2
Jozefina Bogusz, Karol Zrubek, Krzysztof P Rembacz, Przemyslaw Grudnik, Przemyslaw Golik, Malgorzata Romanowska, Benedykt Wladyka, Grzegorz Dubin
PIM1 is an oncogenic kinase overexpressed in a number of cancers where it correlates with poor prognosis. Several studies demonstrated that inhibition of PIM1 activity is an attractive strategy in fighting overexpressing cancers, while distinct structural features of ATP binding pocket make PIM1 an inviting target for the design of selective inhibitors. To facilitate development of specific PIM1 inhibitors, in this study we report three crystal structures of ATP-competitive inhibitors at the ATP binding pocket of PIM1...
October 17, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28934227/hemorrhage-enhances-cytokine-complement-component-3-and-caspase-3-and-regulates-micrornas-associated-with-intestinal-damage-after-whole-body-gamma-irradiation-in-combined-injury
#3
Juliann G Kiang, Joan T Smith, Marsha N Anderson, Thomas B Elliott, Paridhi Gupta, Nagaraja S Balakathiresan, Radha K Maheshwari, Barbara Knollmann-Ritschel
Hemorrhage following whole-body γ-irradiation in a combined injury (CI) model increases mortality compared to whole-body γ-irradiation alone (RI). The decreased survival in CI is accompanied by increased bone marrow injury, decreased hematocrit, and alterations of miRNA in the kidney. In this study, our aim was to examine cytokine homeostasis, susceptibility to systemic bacterial infection, and intestinal injury. More specifically, we evaluated the interleukin-6 (IL-6)-induced stress proteins including C-reactive protein (CRP), complement 3 (C3), Flt-3 ligand, and corticosterone...
2017: PloS One
https://www.readbyqxmd.com/read/28927801/design-synthesis-and-antitumor-activity-of-novel-sorafenib-derivatives-bearing-pyrazole-scaffold
#4
Min Wang, Shan Xu, Huajun Lei, Caolin Wang, Zhen Xiao, Shuang Jia, Jia Zhi, Pengwu Zheng, Wufu Zhu
Four series of Sorafenib derivatives bearing pyrazole scaffold (8a-m, 9a-c, 10a-e and 11a) were synthesized and characterized by NMR and MS. All of the target compounds were evaluated for the cytotoxicity against A549, HepG2, MCF-7, and PC-3 cancer cell lines and some selected compounds were further evaluated for the activity against VEGFR-2/KDR, BRAF, CRAF, c-Met, EGFR and Flt-3 kinases. Compounds 8b and 8i were more active than that of compounds 8h, 9a, especially the IC50 value of compounds 8b on VEGFR-2 kinase was 0...
September 6, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28893953/fate-decision-between-group-3-innate-lymphoid-and-conventional-nk-cell-lineages-by-notch-signaling-in-human-circulating-hematopoietic-progenitors
#5
Seishi Kyoizumi, Yoshiko Kubo, Junko Kajimura, Kengo Yoshida, Tomonori Hayashi, Kei Nakachi, Malcolm A Moore, Marcel R M van den Brink, Yoichiro Kusunoki
The role of Notch signaling in human innate lymphoid cell (ILC) differentiation is unclear, although IL-7 and IL-15 promote differentiation of natural cytotoxicity receptor (NCR) NKp44(+) group 3 ILCs (NCR(+)ILC3s) and conventional NK (cNK) cells from CD34(+) hematopoietic progenitor cells (HPCs) ex vivo. In this study, we analyzed the functions of Notch in the differentiation of NCR(+)ILC3s and cNK cells from human HPC subpopulations circulating in peripheral blood by limiting dilution and clonal assays using high-throughput flow cytometry...
October 15, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28799432/targeted-therapies-in-acute-myeloid-leukemia-a-focus-on-flt-3-inhibitors-and-abt199
#6
REVIEW
Kiran Naqvi, Marina Konopleva, Farhad Ravandi
Acute myeloid leukemia (AML) remains a therapeutic challenge. Despite ongoing research, the standard therapy for AML has not changed significantly in the past four decades. With the identification of cytogenetic and molecular abnormalities, several promising therapeutic agents are currently being investigated. FLT3 mutation is a well-recognized target seen in 30% of the cytogenetically normal AML. More recently, the BCL2 family of anti-apoptotic proteins have also generated great interest as a therapeutic target...
October 2017: Expert Review of Hematology
https://www.readbyqxmd.com/read/28545284/-expression-profiles-and-clinical-implication-of-plasma-chemokines-in-patients-with-stanford-type-a-aortic-dissection
#7
F D Fan, Z J Xu, Q Zhou, D J Wang
Objective: To explore the plasma chemokines expressions and related clinical implication in patients with Stanford type A aortic dissection (AD). Methods: We retrospectively analyzed the data of 65 patients with Stanford type A aortic dissection, hypertensive patients and 11 healthy subjects admitted in our department from October 2013 to December 2014, they were divided into four groups: NH-CON group (11 healthy subjects), H-AD group (29 AD patients with hypertension), NH-AD group (21 AD patients without hypertension), and H-CON group (14 hypertension patients)...
April 24, 2017: Zhonghua Xin Xue Guan Bing za Zhi
https://www.readbyqxmd.com/read/28362701/acute-myeloid-leukemia-aml-upregulation-of-baalc-mn1-mllt11-evi1-gene-cluster-relate-with-poor-overall-survival-and-a-possible-linkage-with-coexpression-of-myc-bcl2-proteins
#8
Ariz Akhter, Fahad Farooq, Ghaleb Elyamany, Muhammad K Mughal, Fariborz Rashid-Kolvear, Meer-Taher Shabani-Rad, Lesley Street, Adnan Mansoor
BACKGROUND: Molecular heterogeneity accounts for the variable and often poor prognosis in acute myeloid leukemia (AML). The current risk stratification strategy in clinical practice is limited to karyotyping and limited molecular studies screening for genetic mutations such as FLT-3 and NPM1. There is opportunity to identify further molecular prognostic markers, which may also lay the groundwork for the development of novel targeted therapies. Complex molecular technologies require transition into widely available laboratory platforms, for better integration into routine clinical practice...
March 30, 2017: Applied Immunohistochemistry & Molecular Morphology: AIMM
https://www.readbyqxmd.com/read/28102569/human-%C3%AE-defensin-3-increases-the-tlr9-dependent-response-to-bacterial-dna
#9
Sarah L McGlasson, Fiona Semple, Heather MacPherson, Mohini Gray, Donald J Davidson, Julia R Dorin
Human β-defensin 3 (hBD3) is a cationic antimicrobial peptide with potent bactericidal activity in vitro. HBD3 is produced in response to pathogen challenge and can modulate immune responses. The amplified recognition of self-DNA by human plasmacytoid dendritic cells has been previously reported, but we show here that hBD3 preferentially enhances the response to bacterial DNA in mouse Flt-3 induced dendritic cells (FLDCs) and in human peripheral blood mononuclear cells. We show the effect is mediated through TLR9 and although hBD3 significantly increases the cellular uptake of both E...
April 2017: European Journal of Immunology
https://www.readbyqxmd.com/read/28081344/peripheral-flt-3-ligand-levels-as-a-pathobiological-parameter-duringthe-clinical-course-of-acute-myeloid-leukemia
#10
Memduh Şahin, İbrahim Celalettin Haznedaroğlu, Demircan Özbalcı
BACKGROUND/AIM: FLT-3 ligand is a growth factor affecting the hematopoietic lineage. The aim of this study was to evaluate the variability of peripheral FLT-3 ligand during the clinical course of acute myeloid leukemia (AML) patients. MATERIALS AND METHODS: Twenty-four patients were enrolled in this study in order to assess alterations in the circulating levels of FLT-3 ligand during the clinical course of AML. RESULTS: We studied the association in the diagnostic period between the FLT-3 ligand and peripheral blood cells together with serum electrolytes...
December 20, 2016: Turkish Journal of Medical Sciences
https://www.readbyqxmd.com/read/27670587/ac220-and-arac-cause-differential-inhibitory-dynamics-in-patient-derived-m5-aml-with-flt3-itd-and-thus-ultimately-distinct-therapeutic-outcomes
#11
Xiaoyu An, Jinping Liu, Na Wang, Di Wang, Liang Huang, Likun Zhang, Jie Cai, Jean-Pierre Wery, Demin Zhou, Jianfeng Zhou, Qi-Xiang Li
Engrafting the bone marrow cells of a patient with M5 acute myeloid leukemia into immunocompromised mice (AM7577) resulted in serially transferrable stable AML and eventual mortality. The disease starts in the bone marrow and then expands to peripheral areas, which is typical of M5 leukemogenesis, where high leukemic burden in blood is coincident with symptoms/mortality. The leukemic cells in the mice had myeloid morphology, phenotypes, and genotypes (including the internal tandem duplication of FMS-like tyrosine kinase receptor 3 gene [FLT3-ITD]) similar to those of the original patient...
January 2017: Experimental Hematology
https://www.readbyqxmd.com/read/27488093/predictive-immunohistochemical-markers-related-to-drug-selection-for-patients-treated-with-sunitinib-or-sorafenib-for-metastatic-renal-cell-cancer
#12
Xin Ma, Lei Wang, Hongzhao Li, Yu Zhang, Yu Gao, Gang Guo, Kan Liu, Qingyu Meng, Chaofei Zhao, Dianjun Wang, Zhigang Song, Xu Zhang
Targeted drug decisions in metastatic renal cell carcinoma are exclusively made on the basis of clinical criteria. We investigated whether these biomarkers (HIF-1α, HIF-2α, CAIX, VEGF, VEGFR1, VEGFR2, VEGFR3, PDGFB, PDGFRA, PDGFRB, CD31, CD44, bcl-xL, KIT, p21, CXCR4, PTEN, (CSF)-1R, RET, and FLT-3) can predictive the different effects between sunitinib and sorafenib treatments and are available to guide targeted drug selection. We enrolled all patients who underwent nephrectomy with postoperative sunitinib- or sorafenib-treatment at our institution from 2007 to 2012...
2016: Scientific Reports
https://www.readbyqxmd.com/read/27453754/metastatic-clear-cell-renal-carcinoma-an-unusual-response-to-temsirolimus-in-second-line-therapy
#13
D L Stanculeanu, A Lazescu, D D Zob, R Bunghez, R Anghel, T D Poteca
Renal cell carcinoma (RCC) represents 3% of all cancers, with the highest incidence occurring in the most developed countries and representing the seventh most common cancer in men and the ninth most common cancer in women. The understanding of the tumor molecular biology and the discovery of new drugs that target molecular pathways have increased the arsenal against advanced renal cell carcinoma and improved the outcomes in the patients suffering from these affections. Studying the molecular signaling that controls the tumor growth and the progression has led to the development of molecular therapies targeting the vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) pathways, resulting in a significant improvement in the overall survival and quality of life...
April 2016: Journal of Medicine and Life
https://www.readbyqxmd.com/read/27356057/acute-radiation-syndrome-severity-score-system-in-mouse-total-body-irradiation-model
#14
Natalia I Ossetrova, Patrick H Ney, Donald P Condliffe, Katya Krasnopolsky, Kevin P Hieber
Radiation accidents or terrorist attacks can result in serious consequences for the civilian population and for military personnel responding to such emergencies. The early medical management situation requires quantitative indications for early initiation of cytokine therapy in individuals exposed to life-threatening radiation doses and effective triage tools for first responders in mass-casualty radiological incidents. Previously established animal (Mus musculus, Macaca mulatta) total-body irradiation (γ-exposure) models have evaluated a panel of radiation-responsive proteins that, together with peripheral blood cell counts, create a multiparametic dose-predictive algorithm with a threshold for detection of ~1 Gy from 1 to 7 d after exposure as well as demonstrate the acute radiation syndrome severity score systems created similar to the Medical Treatment Protocols for Radiation Accident Victims developed by Fliedner and colleagues...
August 2016: Health Physics
https://www.readbyqxmd.com/read/27233615/contact-dependent-abrogation-of-bone-marrow-derived-plasmacytoid-dendritic-cell-differentiation-by-murine-mesenchymal-stem-cells
#15
Holger Hackstein, Inna Tschipakow, Gregor Bein, Philipp Nold, Cornelia Brendel, Nelli Baal
Plasmacytoid dendritic cells (pDCs) are rare central regulators of antiviral immunity and unsurpassed producers of interferon-α (IFN-α). Despite their crucial role as a link between innate and adaptive immunity, little is known about the modulation of pDC differentiation by other bone marrow (BM) cells. In this study, we investigated the modulation of pDC differentiation in Flt-3 ligand (Flt3L)-supplemented BM cultures, using highly purified mesenchymal stem cells (MSCs) that were FACS-isolated from murine BM based on surface marker expression and used after in vitro expansion...
July 15, 2016: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27166856/an-efficient-and-high-yield-method-for-isolation-of-mouse-dendritic-cell-subsets
#16
Pooja Arora, Steven A Porcelli
Dendritic cells (DCs) are professional antigen-presenting cells primarily responsible for acquiring, processing and presenting antigens on antigen presenting molecules to initiate T-cell-mediated immunity. Dendritic cells can be separated into several phenotypically and functionally heterogeneous subsets. Three important subsets of splenic dendritic cells are plasmacytoid, CD8α(Pos) and CD8α(Neg) cells. The plasmacytoid DCs are natural producers of type I interferon and are important for anti-viral T cell immunity...
April 18, 2016: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/27045179/comparison-of-the-crystal-structures-of-the-potent-anticancer-and-anti-angiogenic-agent-regorafenib-and-its-monohydrate
#17
Meng Ying Sun, Su Xiang Wu, Xin Bo Zhou, Jian Ming Gu, Xiu Rong Hu
Regorafenib {systematic name: 4-[4-({[4-chloro-3-(trifluoromethy)phenyl]carbamoyl}amino)-3-fluorophenoxy]-1-methylpyridine-2-carboxamide}, C21H15ClF4N4O3, is a potent anticancer and anti-angiogenic agent that possesses various activities on the VEGFR, PDGFR, raf and/or flt-3 kinase signaling molecules. The compound has been crystallized as polymorphic form I and as the monohydrate, C21H15ClF4N4O3·H2O. The regorafenib molecule consists of biarylurea and pyridine-2-carboxamide units linked by an ether group...
April 2016: Acta Crystallographica. Section C, Structural Chemistry
https://www.readbyqxmd.com/read/27042004/selective-use-of-sorafenib-in-the-treatment-of-thyroid-cancer
#18
REVIEW
Fabián Pitoia, Fernando Jerkovich
Sorafenib is a multiple kinase inhibitor (MKI) approved for the treatment of primary advanced renal cell carcinoma and advanced primary liver cancer. It was recently approved by several health agencies around the world as the first available MKI treatment for radioactive iodine-refractory advanced and progressive differentiated thyroid cancer. Sorafenib targets C-RAF, B-RAF, VEGF receptor-1, -2, -3, PDGF receptor-β, RET, c-kit, and Flt-3. As a multifunctional inhibitor, sorafenib has the potential of inhibiting tumor growth, progression, metastasis, and angiogenesis and downregulating mechanisms that protect tumors from apoptosis and has shown to increase the progression-free survival in several Phase II trials...
2016: Drug Design, Development and Therapy
https://www.readbyqxmd.com/read/26995531/development-of-a-potent-and-selective-flt3-kinase-inhibitor-by-systematic-expansion-of-a-non-selective-fragment-screening-hit
#19
Hirofumi Nakano, Tsukasa Hasegawa, Riyo Imamura, Nae Saito, Hirotatsu Kojima, Takayoshi Okabe, Tetsuo Nagano
A non-selective inhibitor (1) of FMS-like tyrosine kinase-3 (FLT3) was identified by fragment screening and systematically modified to afford a potent and selective inhibitor 26. We confirmed that 26 inhibited the growth of FLT-3-activated human acute myeloid leukemia cell line MV4-11. Our design strategy enabled rapid development of a novel type of FLT3 inhibitor from the hit fragment in the absence of target-structural information.
May 1, 2016: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/26944614/synthesis-and-antiproliferative-activity-of-6-7-disubstituted-4-phenoxyquinoline-derivatives-bearing-the-2-oxo-4-chloro-1-2-dihydroquinoline-3-carboxamide-moiety
#20
Qidong Tang, Xin Zhai, Yayi Tu, Ping Wang, Linxiao Wang, Chunjiang Wu, Wenhui Wang, Hongbo Xie, Ping Gong, Pengwu Zheng
A series of 6,7-disubstituted-4-phenoxyquinoline derivatives bearing the 2-oxo-4-chloro-1,2-dihydroquinoline-3-carboxamide moiety were synthesized, and evaluated for their antiproliferative activity against 5 cancer cell lines (H460, HT-29, MKN-45, A549, and U87MG). Most compounds showed moderate to excellent potency, and compared to foretinib, the most promising analog 42 (c-Met/Flt-3 IC50=1.21/2.15nM) showed a 6.1-fold increase in activity against H460 cell line in vitro. The enzymatic assays (c-Met, VEGFR-2, Flt-3, PDGFR-β, c-Kit, and EGFR) of compound 42 were evaluated in vitro...
April 1, 2016: Bioorganic & Medicinal Chemistry Letters
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