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https://www.readbyqxmd.com/read/29045907/reactive-neutrophil-responses-dependent-on-the-receptor-tyrosine-kinase-c-met-limit-cancer-immunotherapy
#1
Nicole Glodde, Tobias Bald, Debby van den Boorn-Konijnenberg, Kyohei Nakamura, Jake S O'Donnell, Sabrina Szczepanski, Maria Brandes, Sarah Eickhoff, Indrajit Das, Naveen Shridhar, Daniel Hinze, Meri Rogava, Tetje C van der Sluis, Janne J Ruotsalainen, Evelyn Gaffal, Jennifer Landsberg, Kerstin U Ludwig, Christoph Wilhelm, Monika Riek-Burchardt, Andreas J Müller, Christoffer Gebhardt, Richard A Scolyer, Georgina V Long, Viktor Janzen, Michele W L Teng, Wolfgang Kastenmüller, Massimiliano Mazzone, Mark J Smyth, Thomas Tüting, Michael Hölzel
Inhibitors of the receptor tyrosine kinase c-MET are currently used in the clinic to target oncogenic signaling in tumor cells. We found that concomitant c-MET inhibition promoted adoptive T cell transfer and checkpoint immunotherapies in murine cancer models by increasing effector T cell infiltration in tumors. This therapeutic effect was independent of tumor cell-intrinsic c-MET dependence. Mechanistically, c-MET inhibition impaired the reactive mobilization and recruitment of neutrophils into tumors and draining lymph nodes in response to cytotoxic immunotherapies...
October 17, 2017: Immunity
https://www.readbyqxmd.com/read/29045894/from-oncogene-interference-to-neutrophil-immune-modulation
#2
Vincenzo Bronte
Oncogenes can aid tumor progression in a cancer cell-extrinsic way. In this issue of Immunity, Glodde et al. (2017) demonstrate that interference with c-MET tyrosine kinase receptor can relieve neutrophil-dependent immune suppression and unleash the effectiveness of immunotherapy even in the context of c-MET-independent tumors.
October 17, 2017: Immunity
https://www.readbyqxmd.com/read/29045518/negative-hyper-selection-of-metastatic-colorectal-cancer-patients-for-anti-egfr-monoclonal-antibodies-the-pressing-case-control-study
#3
C Cremolini, F Morano, R Moretto, R Berenato, E Tamborini, F Perrone, D Rossini, A Gloghini, A Busico, G Zucchelli, C Baratelli, E Tamburini, M Tampellini, E Sensi, G Fucà, C Volpi, M Milione, M Di Maio, G Fontanini, F De Braud, A Falcone, F Pietrantonio
Background: Refining the selection of metastatic colorectal cancer (mCRC) patients candidates for anti-EGFR monoclonal antibodies beyond RAS and BRAF testing is a challenge of precision oncology. Several uncommon genomic mechanisms of primary resistance, leading to activation of tyrosine kinase receptors other than EGFR or downstream signaling pathways, have been suggested by preclinical and retrospective studies. Patients and methods: We conducted this multicenter, prospective, case-control study to demonstrate the negative predictive impact of a panel of rare genomic alterations (PRESSING panel), including HER2/MET amplifications, ALK/ROS1/NTRK1-3/RET fusions, and HER2/PI3K/PTEN/AKT1 mutations...
September 25, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/29045271/rhabdomyosarcoma-cells-are-susceptible-to-cell-death-by-ldk378-alone-or-in-combination-with-sorafenib-independently-of-anaplastic-lymphoma-kinase-status
#4
Nadezda Dolgikh, Simone Fulda
Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase that is often overexpressed in rhabdomyosarcoma (RMS). However, its oncogenic and functional role in RMS remains unclear. Therefore, we investigated the antitumor activity of LDK378 (ceritinib), a new second-generation ALK inhibitor approved for patients with ALK-positive non-small-cell lung cancers. Here, we report that LDK378 reduces cell viability and induces cell death in RMS cell lines at low micromolar IC50 concentrations irrespective of ALK expression levels or phosphorylation status...
November 2017: Anti-cancer Drugs
https://www.readbyqxmd.com/read/29045250/clinical-decision-making-for-immunotherapy-in-metastatic-renal-cell-carcinoma
#5
Manuela Schmidinger
PURPOSE OF REVIEW: To review the treatment options in metastatic renal cell carcinoma (mRCC) in the light of new immunotherapy results. RECENT FINDINGS: Second-line treatment strategies for treatment of mRCC after progression on first-line VEGF-targeted therapy have recently undergone a major change. Treatment guidelines currently recommend the use of either nivolumab, a programmed cell death 1 (PD-1) inhibitor, or cabozantinib, an inhibitor of multiple receptor tyrosine kinases, as preferred choices...
October 17, 2017: Current Opinion in Urology
https://www.readbyqxmd.com/read/29045015/the-small-molecule-mertk-inhibitor-unc2025-decreases-platelet-activation-and-prevents-thrombosis
#6
Brian R Branchford, Timothy J Stalker, Luke Law, Gilbert Acevedo, Susan Sather, Christine Brzezinski, Katina M Wilson, Katherine Minson, Alisa B Lee-Sherick, Pavel Davizon-Castillo, Christopher Ng, Weihe Zhang, Keith B Neeves, Steven R Lentz, Xiaodong Wang, Stephen V Frye, H Shelton Earp, Deborah DeRyckere, Lawrence F Brass, Douglas K Graham, Jorge A Di Paola
BACKGROUND: Gas6 signals through the TAM (TYRO-3, AXL, MERTK) receptor family mediating platelet activation and thrombus formation via activation of the aggregate-stabilizing αIIb β3 integrin. OBJECTIVE: Here we describe anti-thrombotic effects mediated by UNC2025, a small molecule MERTK tyrosine kinase inhibitor. METHODS: MERTK phosphorylation and downstream signaling were assessed by immunoblot. Light transmission aggregometry, flow cytometry, and microfluidic analysis were used to evaluate the impact of MERTK inhibition on platelet activation and stability of aggregate formation in vitro...
October 17, 2017: Journal of Thrombosis and Haemostasis: JTH
https://www.readbyqxmd.com/read/29044514/ccdc6-the-identity-of-a-protein-known-to-be-partner-in-fusion
#7
REVIEW
Aniello Cerrato, Francesco Merolla, Francesco Morra, Angela Celetti
Coiled Coil Domain Containing 6 gene, CCDC6, was initially isolated as part of a tumorigenic DNA originated by the fusion of CCDC6 with the tyrosine kinase of RET receptor, following a paracentric inversion of chromosome 10. For a long time CCDC6 has been considered as an accidental partner of the RET protooncogene, providing the promoter and the first 101 aa necessary for the constitutive activation of the oncogenic Tyrosine Kinase (TK) RET in thyroid cells. With the advent of more refined diagnostic tools and bioinformatic algorithms, an exponential growth in fusion genes discoveries has allowed the identification of CCDC6 as partner of genes other than RET in different tumor types...
October 16, 2017: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/29044016/drug-induced-hypothyroidism
#8
Leonardo F L Rizzo, Daniela L Mana, Héctor A Serra
The thyroid axis is particularly prone to interactions with a wide variety of drugs, whose list increases year by year. Hypothyroidism is the most frequent consequence of drug-induced thyroid dysfunction. The main mechanisms involved in the development of primary hypothyroidism are: inhibition of the synthesis and/or release of thyroid hormones, immune mechanisms related to the use of interferon and other cytokines, and the induction of thyroiditis associated with the use of tyrosine kinase inhibitors and drugs blocking the receptors for vascular endothelial growth factor...
2017: Medicina
https://www.readbyqxmd.com/read/29043985/from-the-observation-of-atypical-cells-on-blood-smear-to-the-diagnosis-of-mast-cell-leukemia-a-case-report-in-a-79-year-old-woman-consulting-for-anemia
#9
Julien Decker, Sabine Meyer, Véronique Latger-Cannard, Sorin Visanica, Elena Loppinet, Jean-François Lesesve, Blandine Bénet
Mast cell leukemia is an extremely rare disease, which belongs to the systemic mastocytosis group (WHO 2016). We are reporting the case of a 79-year-old woman, without any hematological particular history consulting for hyperthermia, repeated malaise and subacute anemia. Her clinical examination was normal. Unusual cells were seen on blood and bone marrow smears. They represent more than 10% of blood nucleated cells end more than 20% of the bone marrow nucleated cells. Bone marrow immunophenotyping was performed to characterize these cells...
October 18, 2017: Annales de Biologie Clinique
https://www.readbyqxmd.com/read/29043702/n-acetylcysteine-compared-to-metformin-improves-the-expression-profile-of-growth-differentiation-factor-9-and-receptor-tyrosine-kinase-c-kit-in-the-oocytes-of-patients-with-polycystic-ovarian-syndrome
#10
Ebrahim Cheraghi, Malek Soleimani Mehranjani, Seyed Mohammad Ali Shariatzadeh, Mohammad Hossein Nasr Esfahani, Behrang Alani
Background: Paracrine disruption of growth factors in women with polycystic ovarian syndrome (PCOS) results in production of low quality oocyte, especially following ovulation induction. The aim of this study was to investigate the effects of metformin (MET), N-acetylcysteine (NAC) and their combination on the hormonal levels and expression profile of GDF-9, BMP-15 and c-kit, as hallmarks of oocyte quality, in PCOS patients. MATERIALS AND METHODS: This prospective randomized, double-blind, placebo controlled trial aims to study the effects of MET, NAC and their combination (MET+NAC) on expression of GDF-9, BMP-15 and c-kit mRNA in oocytes [10 at the germinal vesicle (GV) stage, 10 at the MI stage, and 10 at the MII stage from per group] derived following ovulation induction in PCOS...
January 2018: International Journal of Fertility & Sterility
https://www.readbyqxmd.com/read/29043363/blocking-probe-as-a-potential-tool-for-detection-of-single-nucleotide-dna-mutations-design-and-performance
#11
M Ali Aboudzadeh, M Sanromán-Iglesias, C H Lawrie, M Grzelczak, L M Liz-Marzán, T Schäfer
Developing strategies to detect single nucleotide DNA mutations associated with treatment decisions in cancer patients from liquid biopsies is a rapidly emerging area of personalized medicine that requires high specificity. Here we report how to design an easy enzyme-free approach that could create a platform for detection of L858R mutation of EGFR that is a predictive biomarker of tyrosine kinase treatment in many cancers. This approach includes the addition of blocking probes with the antisense ssDNA at different blocking positions and different concentrations such as to avoid re-annealing with the respective sense ssDNA...
October 18, 2017: Nanoscale
https://www.readbyqxmd.com/read/29042995/overexpression-of-dominant-negative-ikaros-6-isoform-is-associated-with-resistance-to-tkis-in-patients-with-philadelphia-chromosome-positive-acute-lymphoblastic-leukemia
#12
Changfeng Shao, Jie Yang, Yirong Kong, Cong Cheng, Wei Lu, Hongzai Guan, Haiyan Wang
The clinical significance of the dominant-negative Ikaros 6 (DN-IK6) in the treatment of patients with Philadelphia-positive acute lymphoblastic leukemia (Ph(+)-ALL) with tyrosine kinase inhibitors (TKIs) remains elusive. In the present study, it was demonstrated that DN-IK6 was overexpressed in B-cell (B)-ALL cases compared with T cell-ALL cases at the mRNA and protein levels. Furthermore, nucleotide sequencing revealed that DN-IK6 was due to the deletion of IKAROS family zinc finger 1 exons 4-7. The outcome of patients with Ph(+)-B-ALL with DN-IK6, and treated with TKIs and hyper-cyclophosphamide/vincristine/doxorubicin/dexamethasone regimen were restrospectively evaluated in a 2 year follow-up...
October 2017: Experimental and Therapeutic Medicine
https://www.readbyqxmd.com/read/29042798/crizotinib-a-met-inhibitor-inhibits-growth-migration-and-invasion-of-breast-cancer-cells-in-vitro-and-synergizes-with-chemotherapeutic-agents
#13
Nehad M Ayoub, Kamal M Al-Shami, Mohammad A Alqudah, Nizar M Mhaidat
MET is a receptor tyrosine kinase known for its pleiotropic effects in tumorigenesis. Dysregulations of MET expression and/or signaling have been reported and determined to be associated with inferior outcomes in breast cancer patients rendering MET a versatile candidate for targeted therapeutic intervention. Crizotinib is a multi-targeted small-molecule kinase inhibitor for MET, ALK, and ROS1 kinases. This study evaluated the anti-proliferative, cytotoxic, anti-migratory, and anti-invasive effects of crizotinib in breast cancer cells in vitro...
2017: OncoTargets and Therapy
https://www.readbyqxmd.com/read/29042578/%C3%AE-defensin-1-expression-in-hcv-infected-liver-liver-cancer-an-important-role-in-protecting-hcv-progression-and-liver-cancer-development
#14
Yue-Ming Ling, Jin-Yu Chen, Libin Guo, Chen-Yi Wang, Wen-Ting Tan, Qing Wen, Shu-Dong Zhang, Guo-Hong Deng, Yao Lin, Hang Fai Kwok
β-defensin family plays a role in host defense against viral infection, however its role in HCV infection is still unknown. In this study, we demonstrated that β-defensin 1 was significantly reduced in HCV-infected liver specimens. Treatment with interferon and ribavirin upregulated β-defensin-1, but not other β-defensin tested, with the extent and duration of upregulation associated with treatment response. We investigated β-defensin family expression in liver cancer in publicly available datasets and found that among all the β-defensins tested, only β-defensin 1 was significantly downregulated, suggesting β-defensin 1 plays a crucial role in liver cancer development...
October 17, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29042542/tyrosine-phosphorylation-of-the-garu-e3-ubiquitin-ligase-promotes-gibberellin-signalling-by-preventing-gid1-degradation
#15
Keiichirou Nemoto, Abdelaziz Ramadan, Gen-Ichiro Arimura, Kenichiro Imai, Kentaro Tomii, Kazuo Shinozaki, Tatsuya Sawasaki
Gibberellin (GA) is a major hormone for plant growth and development. GA response is derived from the degradation of DELLA repressor proteins after GA-dependent complex formation of the GID1 GA receptor with DELLA. Genistein is a known tyrosine (Tyr) kinase inhibitor and inhibits DELLA degradation. However, the biological role of Tyr phosphorylation on the GA response remains unclear. Here, we demonstrate that GARU (GA receptor RING E3 ubiquitin ligase) mediates ubiquitin-dependent degradation of GID1, and that the TAGK2 plant Tyr-kinase is a target of genistein and inhibits GARU-GID1A interactions by phosphorylation of GARU at Tyr321...
October 17, 2017: Nature Communications
https://www.readbyqxmd.com/read/29042436/wilms-tumor-protein-dependent-transcription-of-vegf-receptor-2-and-hypoxia-regulate-expression-of-the-testis-promoting-gene-sox9-in-murine-embryonic-gonads
#16
Karin M Kirschner, Lina K Sciesielski, Katharina Krueger, Holger Scholz
The Wilms tumor protein 1 (WT1) has been implicated in the control of several genes in sexual development, but its function in gonad formation is still unclear. Here, we report that WT1 stimulates expression of Kdr, the gene encoding VEGF receptor 2, in murine embryonic gonads. We found that WT1 and KDR are co-expressed in Sertoli cells of the testes and somatic cells of embryonic ovaries. Vivo-morpholino-mediated WT1 knockdown decreased Kdr transcripts in cultured embryonic gonads at multiple developmental stages...
October 17, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29042082/the-proto-oncogene-tyrosine-protein-kinase-src-is-essential-for-macrophage-myofibroblast-transition-during-renal-scarring
#17
Patrick Ming-Kuen Tang, Shuang Zhou, Chun-Jie Li, Jinyue Liao, Jun Xiao, Qing-Ming Wang, Guang-Yu Lian, Jinhong Li, Xiao-Ru Huang, Ka-Fai To, Chi-Fai Ng, Charing Ching-Ning Chong, Ronald Ching-Wa Ma, Tin-Lap Lee, Hui-Yao Lan
Src activation has been associated with fibrogenesis after kidney injury. Macrophage-myofibroblast transition is a newly identified process to generate collagen-producing myofibroblasts locally in the kidney undergoing fibrosis in a TGF-β/Smad3-dependent manner. The potential role of the macrophage-myofibroblast transition in Src-mediated renal fibrosis is unknown. In studying this by RNA sequencing at single-cell resolution, we uncovered a unique Src-centric regulatory gene network as a key underlying mechanism of macrophage-myofibroblast transition...
October 14, 2017: Kidney International
https://www.readbyqxmd.com/read/29041833/healthcare-costs-in-patients-with-advanced-non-small-cell-lung-cancer-and-disease-progression-during-targeted-therapy-a-real-world-observational-study
#18
Karen E Skinner, Ancilla W Fernandes, Mark S Walker, Melissa Pavilack, Ari VanderWalde
AIMS: To assess healthcare costs during treatment with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) and following disease progression in patients with advanced non-small cell lung cancer (NSCLC). METHODS: A retrospective analysis of medical records of US community oncology practices was conducted. Eligible patients had advanced NSCLC (stage IIIB/IV) diagnosed between January 1, 2008 and January 1, 2015, initiated treatment with erlotinib or afatinib (first-line or second-line), and had disease progression...
October 18, 2017: Journal of Medical Economics
https://www.readbyqxmd.com/read/29039762/marine-derived-2-aminoimidazolone-alkaloids-leucettamine-b-related-polyandrocarpamines-inhibit-mammalian-and-protozoan-dyrk-clk-kinases
#19
Nadège Loaëc, Eletta Attanasio, Benoît Villiers, Emilie Durieu, Tania Tahtouh, Morgane Cam, Rohan A Davis, Aline Alencar, Mélanie Roué, Marie-Lise Bourguet-Kondracki, Peter Proksch, Emmanuelle Limanton, Solène Guiheneuf, François Carreaux, Jean-Pierre Bazureau, Michelle Klautau, Laurent Meijer
A large diversity of 2-aminoimidazolone alkaloids is produced by various marine invertebrates, especially by the marine Calcareous sponges Leucetta and Clathrina. The phylogeny of these sponges and the wide scope of 2-aminoimidazolone alkaloids they produce are reviewed in this article. The origin (invertebrate cells, associated microorganisms, or filtered plankton), physiological functions, and natural molecular targets of these alkaloids are largely unknown. Following the identification of leucettamine B as an inhibitor of selected protein kinases, we synthesized a family of analogues, collectively named leucettines, as potent inhibitors of DYRKs (dual-specificity, tyrosine phosphorylation regulated kinases) and CLKs (cdc2-like kinases) and potential pharmacological leads for the treatment of several diseases, including Alzheimer's disease and Down syndrome...
October 17, 2017: Marine Drugs
https://www.readbyqxmd.com/read/29039474/evaluation-of-a-radiocobalt-labelled-affibody-molecule-for-imaging-of-human-epidermal-growth-factor-receptor-3-expression
#20
Maria Rosestedt, Ken G Andersson, Bogdan Mitran, Sara S Rinne, Vladimir Tolmachev, John Löfblom, Anna Orlova, Stefan Ståhl
The human epidermal growth factor receptor 3 (HER3) is involved in the development of cancer resistance towards tyrosine kinase-targeted therapies. Several HER3‑targeting therapeutics are currently under clinical evaluation. Non-invasive imaging of HER3 expression could improve patient management. Affibody molecules are small engineered scaffold proteins demonstrating superior properties as targeting probes for molecular imaging compared with monoclonal antibodies. Feasibility of in vivo HER3 imaging using affibody molecules has been previously demonstrated...
October 11, 2017: International Journal of Oncology
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