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https://www.readbyqxmd.com/read/27911806/permissive-roles-of-cytokines-interleukin-7-and-flt3-ligand-in-mouse-b-cell-lineage-commitment
#1
Lilly von Muenchow, Llucia Alberti-Servera, Fabian Klein, Giuseppina Capoferri, Daniela Finke, Rhodri Ceredig, Antonius Rolink, Panagiotis Tsapogas
Hematopoietic cells are continuously generated throughout life from hematopoietic stem cells, thus making hematopoiesis a favorable system to study developmental cell lineage commitment. The main factors incorporating environmental signals to developing hematopoietic cells are cytokines, which regulate commitment of hematopoietic progenitors to the different blood lineages by acting either in an instructive or a permissive manner. Fms-like tyrosine kinase-3 (Flt3) ligand (FL) and Interleukin-7 (IL-7) are cytokines pivotal for B-cell development, as manifested by the severely compromised B-cell development in their absence...
November 29, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27908881/pre-clinical-studies-of-gilteritinib-a-next-generation-flt3-inhibitor
#2
Lauren Y Lee, Daniela Hernandez, Trivikram Rajkhowa, Samuel C Smith, Jayant Ranganathan Raman, Bao Nguyen, Donald Small, Mark Levis
Activating mutations in the receptor tyrosine kinase FLT3 comprise approximately one-third of genetic lesions in acute myeloid leukemia (AML) and are associated with a poor prognosis. Internal tandem duplication (FLT3-ITD) mutations in particular are associated with a high relapse rate. Although FLT3 tyrosine kinase inhibitors (TKIs) appear to improve clinical outcomes for patients with FLT3-ITD AML, the development of early-generation FLT3 TKIs has been impeded by several obstacles such as low potency and selectivity, myelosuppression, and the emergence of resistance-conferring point mutations...
December 1, 2016: Blood
https://www.readbyqxmd.com/read/27906677/the-implication-of-flt3-amplification-for-flt-targeted-therapeutics-in-solid-tumors
#3
Sung Hee Lim, Sun-Young Kim, Kyung Kim, Hyojin Jang, Soomin Ahn, Kyoung-Mee Kim, Nayoung K D Kim, Woongyang Park, Su Jin Lee, Seung Tae Kim, Se Hoon Park, Joon Oh Park, Young Suk Park, Se-Hoon Lee, Ho Yeong Lim, Keunchil Park, Won Ki Kang, Jeeyun Lee
We investigated the patients with solid cancers harboring Fms-like tyrosine kinase 3 (FLT3) amplification using targeted sequencing of tumor tissue specimen and FISH assay. Simultaneously, FLT3-amplified patient-derived cells (PDCs) were generated to evaluate the sensitivity to FLT3 inhibition. A patient with metastatic colon cancer who was previously treated with more than 3rd line cytotoxic chemotherapy was found to have FLT3 amplification and then received regorafenib showing partial response. In two PDC cell lines with FLT3 amplification, FLT3 mRNA expression was increased, however, the growth of tumor cells was not significantly inhibited by either regorafenib or sorafenib which is known to block the activity FLT3...
November 29, 2016: Oncotarget
https://www.readbyqxmd.com/read/27906185/anti-proliferative-activity-of-the-npm1-interacting-natural-product-avrainvillamide-in-acute-myeloid-leukemia
#4
Vibeke Andresen, Bjarte S Erikstein, Herschel Mukherjee, André Sulen, Mihaela Popa, Steinar Sørnes, Håkon Reikvam, Kok-Ping Chan, Randi Hovland, Emmet McCormack, Øystein Bruserud, Andrew G Myers, Bjørn T Gjertsen
Mutated nucleophosmin 1 (NPM1) acts as a proto-oncogene and is present in ~30% of patients with acute myeloid leukemia (AML). Here we examined the in vitro and in vivo anti-leukemic activity of the NPM1 and chromosome region maintenance 1 homolog (CRM1) interacting natural product avrainvillamide (AVA) and a fully syntetic AVA analog. The NPM1-mutated cell line OCI-AML3 and normal karyotype primary AML cells with NPM1 mutations were significantly more sensitive towards AVA than cells expressing wild-type (wt) NPM1...
December 1, 2016: Cell Death & Disease
https://www.readbyqxmd.com/read/27904650/cabozantinib-in-the-treatment-of-advanced-renal-cell-carcinoma-clinical-trial-evidence-and-experience
#5
REVIEW
Jose Manuel Ruiz-Morales, Daniel Y C Heng
The treatment of metastatic renal cell carcinoma (mRCC) is rapidly changing. During first-line treatment with targeted therapy, patients ultimately develop resistance to therapy and the disease progresses. Recently, cabozantinib has demonstrated a better response rate, progression-free survival and overall survival compared with everolimus after failure of prior targeted therapy in patients with advanced or metastatic renal cell carcinoma (RCC). Cabozantinib is a small-molecule tyrosine kinase inhibitor (TKI)...
December 2016: Therapeutic Advances in Urology
https://www.readbyqxmd.com/read/27899775/-leukemia
#6
Minenori Eguchi-Ishimae, Mariko Eguchi
Leukemia is derived from hematopoietic stem/progenitor cells that have acquired genetic abnormalities, leading to malignant transformation. The basis of therapyfor leukemia is a combination of anti-cancer drugs based on risk stratification. The overall 5-year survival rate in leukemia patients of all ages is still 40%, although it has improved in pediatric patients. Leuke- mia itself is a heterogeneous disease that includes various entities/subtypes with different pathogenic gene aberrations. Selection of the treatment strategylargelydepends on risk stratification, and this in turn is mainlybased on specific recurrent chromosome aberrations...
November 2016: Gan to Kagaku Ryoho. Cancer & Chemotherapy
https://www.readbyqxmd.com/read/27897208/beta-1-integrin-ligation-and-tlr-ligation-enhance-gm-csf-induced-aldh1a2-expression-in-dendritic-cells-but-differentially-regulate-their-anti-inflammatory-properties
#7
Aya Yokota-Nakatsuma, Yoshiharu Ohoka, Hajime Takeuchi, Si-Young Song, Makoto Iwata
Retinoic acid (RA)-producing CD103(+) mature dendritic cells (DCs) in mesenteric lymph nodes (MLNs) play crucial roles in gut immunity. GM-CSF and RA contribute to the expression of the RA-producing enzyme ALDH1A2. However, additional signals appeared to be required for inducing ALDH1A2(high) mature DCs from immature DCs. We found here that TLR ligands (Ls) and immobilized E-cadherin could provide such signals in FLT3-L-generated bone marrow (BM)-derived DCs after treatment with GM-CSF and the RA receptor agonist Am80...
November 29, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27893163/sorafenib-and-azacitidine-as-salvage-therapy-for-relapse-of-flt3-itd-mutated-aml-after-allo-sct
#8
Christina Rautenberg, Kathrin Nachtkamp, Ariane Dienst, Pia Verena Schmidt, Claudia Heyn, Mustafa Kondakci, Ulrich Germing, Rainer Haas, Guido Kobbe, Thomas Schroeder
OBJECTIVE: Patients with acute myeloid leukemia (AML) carrying FLT3-ITD mutations (FLT3-ITD+) who relapse after allogeneic 3transplantation (allo-SCT) have a very dismal prognosis with the currently available treatment options. METHODS: We treated 8 patients with FLT3-ITD+ AML who had relapsed in median 91 days (range, 28 - 249) following allo-SCT with a combination of the multikinase inhibitor Sorafenib and the DNA methyltransferase inhibitor Azacitidine (Aza)...
November 28, 2016: European Journal of Haematology
https://www.readbyqxmd.com/read/27890252/aml-in-2016-where-we-are-now
#9
REVIEW
Jacob M Rowe
A high relapse rate for patients with acute myeloid leukemia (AML) is still a major barrier to the long-term survival of these patients. Nevertheless, considerable progress has been made both in the biology and therapy of the disease. Specifically, progress has been made in the areas of integrated genomic analysis for prognosis, the widening application of minimal residual disease (MRD) monitoring in clinical practice, the development of new agents, and the increasing use of drugs, such as IDH and FLT3 inhibitors, as a bridge to transplant...
December 2016: Best Practice & Research. Clinical Haematology
https://www.readbyqxmd.com/read/27881871/diagnosis-and-relapse-cytogenetically-normal-acute-myelogenous-leukemia-without-flt3-itd-or-mll-ptd
#10
W Chien, Q-Y Sun, L-W Ding, A Mayakonda, S Takao, L Liu, S L Lim, K T Tan, M Garg, A De Sousa Maria Varela, J Xiao, N Jacob, K Behrens, C Stocking, M Lill, V Madan, N Hattori, G Sigal, S Ogawa, S Wakita, T Ikezoe, L-Y Shih, T Alpermann, T Haferlach, H Yang, H P Koeffler
Leukemia accepted article preview online, 24 November 2016. doi:10.1038/leu.2016.343.
November 24, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/27879203/fetal-and-neonatal-hematopoietic-progenitors-are-functionally-and-transcriptionally-resistant-to-flt3-itd-mutations
#11
Shaina N Porter, Andrew S Cluster, Wei Yang, Kelsey A Busken, Riddhi M Patel, Jiyeon A Ryoo, Jeffrey A Magee
The FLT3 Internal Tandem Duplication (FLT3(ITD)) mutation is common in adult acute myeloid leukemia (AML) but rare in early childhood AML. It is not clear why this difference occurs. Here we show that Flt3(ITD) and cooperating Flt3(ITD)/Runx1 mutations cause hematopoietic stem cell depletion and myeloid progenitor expansion during adult but not fetal stages of murine development. In adult progenitors, FLT3(ITD) simultaneously induces self-renewal and myeloid commitment programs via STAT5-dependent and STAT5-independent mechanisms, respectively...
November 23, 2016: ELife
https://www.readbyqxmd.com/read/27872090/mutational-landscape-of-pediatric-acute-lymphoblastic-leukemia
#12
LingWen Ding, Qiao-Yang Sun, Kar-Tong Tan, Wenwen Chien, Anand Mayakonda Thippeswamy, Allen Yeoh Eng Juh, Norihiko Kawamata, Yasunobu Nagata, Jin-Fen Xiao, Xin-Yi Loh, De-Chen Lin, Manoj Garg, Su-Lin Lim, Li-Zhen Liu, Vikas Madan, Yan-Yi Jiang, Liang Xu, Masashi Sanada, Lucia Torres Fernández, Hema Preethi, Michael Lill, Hagop Kantarjian, S M Kornblau, Satoru Miyano, Seishi Ogawa, Der-Cherng Liang, Lee-Yung Shih, Henry Yang, H Phillip Koeffler
Current standard of care for patients with pediatric acute lymphoblastic leukemia (ALL) is mainly effective, with high remission rates after treatment. However, the genetic perturbations that give rise to this disease remain largely undefined, limiting the ability to address resistant tumors or develop less toxic targeted therapies. Here we report the use of next generation sequencing to interrogate the genetic and pathogenic mechanisms of 240 pediatric ALL cases with their matched remission samples. Commonly mutated genes fell into several categories, including RAS/receptor tyrosine kinases, epigenetic regulators, transcription factors involved in lineage commitment and the p53/cell cycle pathway...
November 21, 2016: Cancer Research
https://www.readbyqxmd.com/read/27872058/a-randomised-assessment-of-adding-the-kinase-inhibitor-lestaurtinib-to-1st-line-chemotherapy-for-flt3-mutated-aml
#13
Steven Knapper, Nigel Russell, Amanda Gilkes, Robert K Hills, Rosemary E Gale, James D Cavenagh, Gail Jones, Lars Kjeldsen, Michael R Grunwald, Ian Thomas, Heiko Konig, Mark J Levis, Alan K Burnett
The clinical benefit of adding FLT3-directed small molecule therapy to standard first-line treatment of acute myeloid leukemia (AML) has not yet been established. As part of the UK AML15 and 17 trials, patients with previously-untreated AML and confirmed FLT3-activating mutations, mostly aged <60 years, were randomised to receive oral Lestaurtinib (CEP701), or not, following each of four cycles of induction and consolidation chemotherapy. Lestaurtinib was commenced 2 days after completing chemotherapy and administered in cycles of up to 28 days...
November 21, 2016: Blood
https://www.readbyqxmd.com/read/27872057/how-i-treat-flt3-mutated-aml
#14
Keith W Pratz, Mark Levis
FLT3-mutated acute myeloid leukemia (AML), despite not being recognized as a distinct entity in the World Health Organization (WHO) classification system, is readily recognized as a particular challenge by clinical specialists who treat acute leukemia. This is especially true with regards to the patients harboring the most common type of FLT3 mutation, the internal tandem duplication (FLT3-ITD) mutation. Here we present four patient cases from our institution and discuss how our management reflects what we have learned about this subtype of the disease...
November 21, 2016: Blood
https://www.readbyqxmd.com/read/27870947/subcellular-localization-of-the-flt3-itd-oncogene-plays-a-significant-role-in-the-production-of-nox-and-p22-phox-derived-reactive-oxygen-species-in-acute-myeloid-leukemia
#15
Jennifer N Moloney, Joanna Stanicka, Thomas G Cotter
Internal tandem duplication of the juxtamembrane domain of FMS-like tyrosine kinase 3 (FLT3-ITD) receptor is the most prevalent FLT3 mutation accounting for 20% of acute myeloid leukemia (AML) patients. FLT3-ITD mutation results in ligand-independent constitutive activation of the receptor at the plasma membrane and 'impaired trafficking' of the receptor in compartments of the endomembrane system, such as the endoplasmic reticulum (ER). FLT3-ITD expressing cells have been shown to generate increased levels of reactive oxygen species (ROS), in particular NADPH oxidase (NOX)-generated ROS which act as pro-survival signals...
November 11, 2016: Leukemia Research
https://www.readbyqxmd.com/read/27868021/rational-for-targeting-the-hedgehog-signalling-pathway-in-acute-myeloid-leukemia-with-flt3-mutation
#16
COMMENT
Didier Bouscary
No abstract text is available yet for this article.
October 2016: Annals of Translational Medicine
https://www.readbyqxmd.com/read/27863392/discovery-of-bpr1k871-a-quinazoline-based-multi-kinase-inhibitor-for-the-treatment-of-aml-and-solid-tumors-rational-design-synthesis-in-vitro-and-in-vivo-evaluation
#17
Yung Chang Hsu, Mohane Selvaraj Coumar, Wen-Chieh Wang, Hui-Yi Shiao, Yi-Yu Ke, Wen-Hsing Lin, Ching-Chuan Kuo, Chun-Wei Chang, Fu-Ming Kuo, Pei-Yi Chen, Sing-Yi Wang, An-Siou Li, Chun-Hwa Chen, Po-Chu Kuo, Ching-Ping Chen, Ming-Hsine Wu, Chen-Lung Huang, Kuei-Jung Yen, Yun-I Chang, John T-A Hsu, Chiung-Tong Chen, Teng-Kuang Yeh, Jen-Shin Song, Chuan Shih, Hsing-Pang Hsieh
The design and synthesis of a quinazoline-based, multi-kinase inhibitor for the treatment of acute myeloid leukemia (AML) and other malignancies is reported. Based on the previously reported furanopyrimidine 3, quinazoline core containing lead 4 was synthesized and found to impart dual FLT3/AURKA inhibition (IC50 = 127/5 nM), as well as improved physicochemical properties. A detailed structure-activity relationship study of the lead 4 allowed FLT3 and AURKA inhibition to be finely tuned, resulting in AURKA selective (5 and 7; 100-fold selective over FLT3), FLT3 selective (13; 30-fold selective over AURKA) and dual FLT3/AURKA selective (BPR1K871; IC50 = 19/22 nM) agents...
November 15, 2016: Oncotarget
https://www.readbyqxmd.com/read/27863389/nt1721-a-novel-epidithiodiketopiperazine-exhibits-potent-in-vitro-and-in-vivo-efficacy-against-acute-myeloid-leukemia
#18
Claudia M Kowolik, Min Lin, Jun Xie, Larry E Overman, David A Horne
Acute myeloid leukemia (AML) is an aggressive malignancy characterized by heterogeneous genetic and epigenetic changes in hematopoietic progenitors that lead to abnormal self-renewal and proliferation. Despite high initial remission rates, prognosis remains poor for most AML patients, especially for those harboring internal tandem duplication (ITD) mutations in the fms-related tyrosine kinase-3 (FLT3). Here, we report that a novel epidithiodiketopiperazine, NT1721, potently decreased the cell viability of FLT3-ITD+ AML cell lines, displaying IC50 values in the low nanomolar range, while leaving normal CD34+ bone marrow cells largely unaffected...
November 15, 2016: Oncotarget
https://www.readbyqxmd.com/read/27861804/cd103-cd11b-salivary-gland-dendritic-cells-have-antigen-cross-presenting-capacity
#19
Lu Lu, Yukinori Tanaka, Naoto Ishii, Takashi Sasano, Shunji Sugawara
Dendritic cells (DCs) in lymphoid and non-lymphoid tissues are professional antigen-presenting cells that are essential for effective immunity and tolerance. However, the presence and characteristics of DCs in steady-state salivary glands (SGs) currently remain unknown. We herein identified CD64(-) CD11c(+) classical DCs (cDCs) as well as CD64(+) macrophages among CD45(+) MHC class II(+) antigen-presenting cells in steady-state murine SGs. SG cDCs were divided into CD103(+) CD11b(-) and CD103(-) CD11b(+) cDCs...
November 11, 2016: European Journal of Immunology
https://www.readbyqxmd.com/read/27842445/cabozantinib-in-genitourinary-malignancies
#20
Tian Zhang, Se Eun Park, Cierra Hong, Daniel J George
Cabozantinib inhibits a variety of cellular receptors including VEGFR1-3, MET, AXL, RET, FLT3 and KIT. These signaling pathways have been shown to be important in genitourinary malignancies. Along its clinical development, it has shown most activity in advanced renal cell carcinoma; the METEOR study compared cabozantinib to everolimus and showed clinically and statistically significant improvements in both progression-free survival and overall survival. Herein, we review the development of cabozantinib in the genitourinary malignancies of renal cell carcinoma, prostate adenocarcinoma and urothelial carcinoma...
November 15, 2016: Future Oncology
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