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https://www.readbyqxmd.com/read/28643921/whole-exome-sequencing-identified-a-variant-in-eftud2-gene-in-establishing-a-genetic-diagnosis
#1
S Rengasamy Venugopalan, E G Farrow, M Lypka
OBJECTIVES: Craniofacial anomalies are complex and have an overlapping phenotype. Mandibulofacial Dysostosis and Oculo-Auriculo-Vertebral Spectrum are conditions that share common craniofacial phenotype and present a challenge in arriving at a diagnosis. In this report, we present a case of female proband who was given a differential diagnosis of Treacher Collins syndrome or Hemifacial Microsomia without certainty. Prior genetic testing reported negative for 22q deletion and FGFR screenings...
June 2017: Orthodontics & Craniofacial Research
https://www.readbyqxmd.com/read/28643912/mouse-models-for-the-study-of-cranial-base-growth-and-anomalies
#2
REVIEW
S R Vora
The cranial base is a central and integral component of the cranioskeleton, yet little is known about its growth. Despite the dissimilarities between human and murine cranioskeletal form, mouse models are proving instrumental in studying craniofacial growth. The objectives of this review are to summarize recent findings from numerous mouse models that display growth defects in one or more cranial base synchondroses, with accompanying changes in chondrocyte cellular zones. Many of these models also display altered growth of the cranial vault and/or the facial region...
June 2017: Orthodontics & Craniofacial Research
https://www.readbyqxmd.com/read/28640125/targeted-sequencing-in-fgf-fgfr-genes-and-association-analysis-of-variants-for-mandibular-prognathism
#3
Xueyan Xiong, Shuyuan Li, Ying Cai, Fengshan Chen
To identify variants of the genes in fibroblast growth factors/fibroblast growth factor receptors (FGF/FGFR) signal pathway that predispose to mandibular prognathism (MP) in the general Chinese population systematically.Targeted sequencing of the FGF/FGFR genes was conducted in 176 MP individuals and 155 class I malocclusion controls. The associations of common and rare variants with MP as a categorical phenotype and also continuous malocclusion phenotypes generated by principal component (PC) analysis were analyzed...
June 2017: Medicine (Baltimore)
https://www.readbyqxmd.com/read/28630215/mechanisms-of-primary-drug-resistance-in-fgfr1-amplified-lung-cancer
#4
Florian Malchers, Meryem Seda Ercanoglu, Daniel Schütte, Roberta Castiglione, Verena Tischler, Sebastian Michels, Ilona Dahmen, Johannes Brägelmann, Roopika Menon, Johannes M Heuckmann, Julie George, Sascha Ansén, Martin L Sos, Alex Soltermann, Martin Peifer, Jurgen Wolf, Reinhard Büttner, Roman K Thomas
<br />The 8p12-p11 locus is frequently amplified in squamous cell lung cancer (SQLC); the receptor tyrosine kinase fibroblast growth factor receptor 1 (FGFR1) being one of the most prominent targets of this amplification. Thus, small molecules inhibiting FGFRs have been employed to treat FGFR1-amplified SQLC. However, only about 11% of such FGFR1-amplified tumors respond to single agent FGFR inhibition and several tumors exhibited insufficient tumor shrinkage, compatible with the existence of drug-resistant tumor cells...
June 19, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28629128/interactions-between-a-heparin-trisaccharide-library-and-fgf-1-analyzed-by-nmr-methods
#5
María José García-Jiménez, Sergio Gil-Caballero, Ángeles Canales, Jesús Jiménez-Barbero, José L de Paz, Pedro M Nieto
FGF-1 is a potent mitogen that, by interacting simultaneously with Heparan Sulfate Glycosaminoglycan HSGAG and the extracellular domains of its membrane receptor (FGFR), generates an intracellular signal that finally leads to cell division. The overall structure of the ternary complex Heparin:FGF-1:FGFR has been finally elucidated after some controversy and the interactions within the ternary complex have been deeply described. However, since the structure of the ternary complex was described, not much attention has been given to the molecular basis of the interaction between FGF-1 and the HSGAG...
June 17, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28624695/first-in-human-phase-i-study-of-oral-s49076-a-unique-met-axl-fgfr-inhibitor-in-advanced-solid-tumours
#6
Jordi Rodon, Sophie Postel-Vinay, Antoine Hollebecque, Paolo Nuciforo, Analia Azaro, Valérie Cattan, Lucie Marfai, Isabelle Sudey, Karl Brendel, Audrey Delmas, Stéphanie Malasse, Jean-Charles Soria
BACKGROUND AND OBJECTIVES: S49076 is a novel ATP-competitive tyrosine kinase inhibitor of MET, AXL and FGFR with a unique selectivity profile. A phase I open-label study was undertaken to establish the tolerability profile and determine the recommended dose (RD) and administration schedule. MATERIALS AND METHODS: Patients with advanced solid tumours received S49076 orally once-daily (qd) or twice-daily (bid) in continuous 21-day cycles at escalating doses guided by a 3 + 3 design and followed by an expansion phase at the RD...
June 15, 2017: European Journal of Cancer
https://www.readbyqxmd.com/read/28621531/parallels-and-distinctions-in-fgfr-vegfr-and-egfr-mechanisms-of-transmembrane-signaling
#7
Sarvenaz Sarabipour
Receptor tyrosine kinase (RTK) signal transduction is essential in human skeletal, nervous, and vascular development, in homeostasis, and in disease. RTKs are activated by dimerization in the plasma membrane. The mechanisms of receptor dimerization and activation are multifaceted and complex, and unraveling them remains challenging. Most studies of RTKs have been devoted to crystallographic analysis of their isolated extracellular domain and biochemical analysis of the catalytic domain. However, the past few years have seen direct biophysical studies of (intact) RTK dimerization in native membranes lead to significant progress in our fundamental understanding of the mechanisms of their signal transduction across the plasma membrane...
June 16, 2017: Biochemistry
https://www.readbyqxmd.com/read/28619752/the-met-axl-fgfr-inhibitor-s49076-impairs-aurora-b-activity-and-improves-the-antitumor-efficacy-of-radiotherapy
#8
Céline Clémenson, Cyrus Chargari, Winchygn Liu, Michele Mondini, Charles Ferté, Mike F Burbridge, Valérie Cattan, Anne Jacquet-Bescond, Eric Deutsch
Several therapeutic agents targeting HGF/MET signaling are under clinical development as single agents or in combination, notably with anti-EGFR therapies in non-small cell lung cancer (NSCLC). However, despite increasing data supporting a link between MET, irradiation and cancer progression, no data regarding the combination of MET-targeting agents and radiotherapy are available from the clinic. S49076 is an oral ATP-competitive inhibitor of MET, AXL and FGFR1-3 receptors that is currently in phase I/II clinical trials in combination with gefinitib in NSCLC patients whose tumors show resistance to EGFR inhibitors...
June 15, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28619642/polysaccharides-and-their-depolymerized-fragments-from-costaria-costata-molecular-weight-and-sulfation-dependent-anticoagulant-and-fgf-fgfr-signal-activating-activities
#9
Ningning Hou, Meng Zhang, Yingjie Xu, Zhongmin Sun, Jing Wang, Lijuan Zhang, Quanbin Zhang
Crude polysaccharides from Costaria costata were extracted by hot water and further fractionated by anion exchange chromatography into three polysaccharide fractions. Three low molecular weight fragments were then prepared by degradation of the polysaccharides with hydrogen peroxide and ascorbic acid. The structural features of the polysaccharides and their low molecular weight fragments were elucidated for the first time based on the HGPC, FT-IR, NMR, MS, monosaccharide composition, and other chemical analyses...
June 13, 2017: International Journal of Biological Macromolecules
https://www.readbyqxmd.com/read/28615371/a-phase-1b-open-label-multicentre-study-of-azd4547-in-patients-with-advanced-squamous-cell-lung-cancers
#10
Paul K Paik, Ronglai Shen, Michael F Berger, David Ferry, Jean-Charles Soria, Alastair Mathewson, Claire Rooney, Neil R Smith, Marie Cullberg, Elaine Kilgour, Donal Landers, Paul Frewer, A Nigel Brooks, Fabrice André
Squamous cell lung cancers (SQCLC) account for 25% of all NSCLCs, yet the prognosis of these patients is poor and treatment options are limited. Amplified FGFR1 is one of the most common oncogenic events in SQCLCs, occurring in ~20% of cases. AZD4547 is a potent and selective FGFR1-3 inhibitor with anti-tumor activity in FGFR1 amplified SQCLC cell lines and patient-derived xenografts. <br /><br />Experimental Design: Based on these data, we performed a phase 1 study of AZD4547 in patients with previously treated stage IV FGFR1 amplified SQCLCs (NCT00979134)...
June 14, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28611104/cisplatin-increases-sensitivity-to-fgfr-inhibition-in-patient-derived-xenograft-models-of-lung-squamous-cell-carcinoma
#11
Clare E Weeden, Aliaksei Z Holik, Richard J Young, Stephen B Ma, Jean-Marc Garnier, Stephen B Fox, Phillip Antippa, Louis B Irving, Daniel P Steinfort, Gavin M Wright, Prudence A Russell, Matthew E Ritchie, Christopher J Burns, Benjamin Solomon, Marie-Liesse Asselin-Labat
Lung squamous cell carcinoma (SqCC) is a molecularly complex and genomically unstable disease. No targeted therapy is currently approved for lung SqCC, although potential oncogenic drivers of SqCC have been identified, including amplification of the fibroblast growth factor receptor 1 (FGFR1). Reports from a recently completed clinical trial indicate low response rates in patients treated with FGFR tyrosine kinase inhibitors, suggesting inadequacy of FGFR1 amplification as a biomarker of response, or the need for combination treatment...
June 13, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28600887/therapeutic-effects-of-fgf23-c-tail-fc-in-a-murine-pre-clinical-model-of-x-linked-hypophosphatemia-via-the-selective-modulation-of-phosphate-reabsorption
#12
Kristen Johnson, Kymberly Levine, Joseph Sergi, Jean Chamoun, Rachel Roach, Jackie Vekich, Mike Favis, Mark Horn, Xianjun Cao, Brian Miller, William Snyder, Dikran Aivazian, William Reagan, Edwin Berryman, Jennifer Colangelo, Victoria Markiewicz, Cedo Bagi, Thomas P Brown, Anthony Coyle, Moosa Mohammadi, Jeanne Magram
Fibroblast growth factor 23 (FGF23) is the causative factor of X-linked hypophosphatemia (XLH), a genetic disorder effecting 1:20,000 that is characterized by excessive phosphate excretion, elevated FGF23 levels and a rickets/osteomalacia phenotype. FGF23 inhibits phosphate reabsorption and suppresses 1α,25-dihydroxyvitamin D (1,25D) biosynthesis, analytes that differentially contribute to bone integrity and deleterious soft tissue mineralization. As inhibition of ligand broadly modulates downstream targets, balancing efficacy and unwanted toxicity is difficult when targeting the FGF23 pathway...
June 10, 2017: Journal of Bone and Mineral Research: the Official Journal of the American Society for Bone and Mineral Research
https://www.readbyqxmd.com/read/28598558/conserved-signaling-mechanisms-in-drosophila-heart-development
#13
REVIEW
Shaad M Ahmad
Signal transduction through multiple distinct pathways regulates and orchestrates the numerous biological processes comprising heart development. This review outlines the roles of the FGFR, EGFR, Wnt, BMP, Notch, Hedgehog, Slit/Robo and other signaling pathways during four sequential phases of Drosophila cardiogenesis-mesoderm migration, cardiac mesoderm establishment, differentiation of the cardiac mesoderm into distinct cardiac cell types, and morphogenesis of the heart and its lumen based on the proper positioning and cell shape changes of these differentiated cardiac cells-and illustrates how these same cardiogenic roles are conserved in vertebrates...
June 9, 2017: Developmental Dynamics: An Official Publication of the American Association of Anatomists
https://www.readbyqxmd.com/read/28598150/high-yield-site-specific-conjugation-of-fibroblast-growth-factor-1-with-monomethylauristatin-e-via-cysteine-flanked-by-basic-residues
#14
Michal Lobocki, Malgorzata Zakrzewska, Anna Szlachcic, Mateusz Adam Krzyscik, Aleksandra Sokolowska-Wedzina, Jacek Otlewski
Site-specific conjugation is a leading trend in the development of protein conjugates, including antibody-drug conjugates (ADCs), suitable for targeted cancer therapy. Here, we present a very efficient strategy for specific attachment of a cytotoxic drug to fibroblast growth factor 1 (FGF1), a natural ligand of FGF receptors (FGFRs), which are overexpressed in several types of lung, breast and gastric cancers and are therefore an attractive molecular target. Recently we showed that FGF1 fused to monomethylauristatin E (vcMMAE) was highly cytotoxic to cells presenting FGFRs on their surface and could be used as a targeting agent alternative to an antibody...
June 9, 2017: Bioconjugate Chemistry
https://www.readbyqxmd.com/read/28595297/fgfr2-mutations-in-bent-bone-dysplasia-syndrome-activate-nucleolar-stress-and-perturb-cell-fate-determination
#15
Cynthia L Neben, Creighton T Tuzon, Xiaojing Mao, Fides D Lay, Amy E Merrill
Fibroblast growth factor (FGF) signaling promotes self-renewal in progenitor cells by encouraging proliferation and inhibiting cellular senescence. Yet, these beneficial effects can be hijacked by disease-causing mutations in FGF receptor (FGFR) during embryogenesis. By studying dominant FGFR2 mutations that are germline in Bent Bone Dysplasia Syndrome (BBDS), we reveal a mechanistic connection between FGFR2, ribosome biogenesis, and cellular stress that links cell fate determination to disease pathology. We previously showed that FGFR2 mutations in BBDS, which amplify nucleolar targeting of FGFR2, activate ribosomal DNA (rDNA) transcription and delay differentiation in osteoprogenitor cells and patient-derived bone...
June 8, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28589492/a-phase-1-study-of-ly2874455-an-oral-selective-pan-fgfr-inhibitor-in-patients-with-advanced-cancer
#16
Michael Michael, Yung-Jue Bang, Young Suk Park, Yoon-Koo Kang, Tae Min Kim, Oday Hamid, Donald Thornton, Sonya C Tate, Eyas Raddad, Jeanne Tie
BACKGROUND: We report here a phase 1 study of LY2874455, a potent oral selective pan-fibroblast growth factor receptor (FGFR) inhibitor. OBJECTIVE: The primary objective was to determine the recommended phase 2 dosing (RP2D). Secondary objectives included determining toxicity, antitumor activity, pharmacokinetics (PK), and pharmacodynamic (PD) properties of LY2874455. PATIENTS AND METHODS: This study comprised two parts: (a) dose escalation with 3 + 3 cohorts in patients with solid tumors and (b) dose-expansion cohorts in patients with gastric cancer (GC) and non-small cell lung cancer (NSCLC)...
June 6, 2017: Targeted Oncology
https://www.readbyqxmd.com/read/28586032/a-sketch-of-known-and-novel-mycn-associated-mirna-networks-in-neuroblastoma
#17
Francesca Megiorni, Moreno Colaiacovo, Samantha Cialfi, Heather P McDowell, Alessandro Guffanti, Simona Camero, Armando Felsani, Paul D Losty, Barry Pizer, Rajeev Shukla, Carlo Cappelli, Eva Ferrara, Antonio Pizzuti, Anna Moles, Carlo Dominici
Neuroblastoma (NB) originates from neural crest-derived precursors and represents the most common childhood extracranial solid tumour. MicroRNAs (miRNAs), a class of small non-coding RNAs that participate in a wide variety of biological processes by regulating gene expression, appear to play an essential role within the NB context. High-throughput next generation sequencing (NGS) was applied to study the miRNA transcriptome in a cohort of NB tumours with and without MYCN-amplification (MNA and MNnA, respectively) and in dorsal root ganglia (DRG), as a control...
June 6, 2017: Oncology Reports
https://www.readbyqxmd.com/read/28583899/statins-do-not-inhibit-the-fgfr-signaling-in-chondrocytes
#18
B Fafilek, M Hampl, N Ricankova, I Vesela, L Balek, M Kunova Bosakova, I Gudernova, M Varecha, M Buchtova, P Krejci
OBJECTIVE: Statins are widely used drugs for cholesterol lowering, which were recently found to counteract the effects of aberrant fibroblast growth factor receptor (FGFR3) signaling in cell and animal models of FGFR3-related chondrodysplasia. This opened an intriguing therapeutic possibility for human dwarfing conditions caused by gain-of-function mutations in FGFR3, although the mechanism of statin action on FGFR3 remains unclear. Here, we determine the effect of statins on FGFR signaling in chondrocytes...
June 3, 2017: Osteoarthritis and Cartilage
https://www.readbyqxmd.com/read/28564583/fibroblast-growth-factors-fgfs-in-cancer-fgf-traps-as-a-new-therapeutic-approach
#19
REVIEW
Marco Presta, Paola Chiodelli, Arianna Giacomini, Marco Rusnati, Roberto Ronca
Originally characterized as angiogenic factors, fibroblast growth factors (FGFs) are pleiotropic factors that exert autocrine and paracrine functions on tumor and stromal cells. Thus, they may represent key players in the complex crosstalk among angiogenesis, inflammation, tumor growth, and drug resistance, all contributing to tumor progression. Given the multiple activities of FGFs, inhibitors of the FGF/FGFR system may act as "two compartment" targeting drugs able to exert a deep impact on the growth of FGF/FGFR-driven tumors...
May 28, 2017: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28558791/receptor-tyrosine-kinases-play-a-significant-role-in-human-oligodendrocyte-inflammation-and-cell-death-associated-with-the-lyme-disease-bacterium-borrelia-burgdorferi
#20
Geetha Parthasarathy, Mario T Philipp
BACKGROUND: In previous studies, human oligodendrocytes were demonstrated to undergo apoptosis in the presence of Borrelia burgdorferi under an inflammatory milieu. Subsequently, we determined that the MEK/ERK pathway played a significant role in triggering downstream inflammation as well as apoptosis. However, the identity of receptors triggered by exposure to B. burgdorferi and initiating signaling events was unknown. METHODS: In this study, we explored the role of several TLR and EGFR/FGFR/PDGFR tyrosine kinase pathways in inducing inflammation in the presence of B...
May 30, 2017: Journal of Neuroinflammation
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