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https://www.readbyqxmd.com/read/29045509/the-antibody-drug-conjugate-target-landscape-across-a-broad-range-of-tumour-types
#1
K L Moek, D J A de Groot, E G E de Vries, R S N Fehrmann
Background: Antibody-drug conjugates (ADCs), consisting of an antibody designed against a specific target at the cell membrane linked with a cytotoxic agent, are an emerging class of therapeutics. Since ADC tumour cell targets do not have to be drivers of tumour growth, ADCs are potentially relevant for a wide range of tumours currently lacking clear oncogenic drivers. Therefore, we aimed to define the landscape of ADC targets in a broad range of tumours. Materials and methods: PubMed and ClinicalTrials...
September 25, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/29040969/comparison-of-igh-profile-signals-using-t-4-14-and-igh-break-apart-probes-by-fish-in-multiple-myeloma
#2
Thomas Smol, Agnès Daudignon
We compared immunoglobulin heavy chain gene (IGH) signal patterns in multiple myeloma (MM) using the FGFR3-IGH and the IGH break-apart probes to facilitate their understanding and analysis. Forty-nine patients with MM were studied. FISH was performed on samples sorted with an FGFR3-IGH dual-color, dual-fusion translocation probe and an IGH dual-color break-apart rearrangement probe. The IGH deletions were found in 7 MM analyzed with the FGFR3-IGH probe and all confirmed by the IGH break-apart probe. The additional IGH signals were associated with different patterns using the IGH break-apart probe: a normal pattern in 9 cases, trisomy 14 in 3 cases, and splits of IGH in 7 cases...
October 18, 2017: Cytogenetic and Genome Research
https://www.readbyqxmd.com/read/29040558/constitutively-active-fgfr3-disrupts-primary-cilium-length-and-ift20-trafficking-in-various-chondrocyte-models-of-achondroplasia
#3
Ludovic Martin, Nabil Kaci, Valentin Estibals, Nicolas Goudin, Meriem Garfa-Traore, Catherine Benoist-Lasselin, Emilie Dambroise, Laurence Legeai-Mallet
FGFR3 (fibroblast growth factor receptor 3) gain-of-function mutations cause dwarfisms, including achondroplasia (ACH) and thanatophoric dysplasia (TD). The constitutive activation of FGFR3 disrupts the normal process of skeletal growth. Bone-growth anomalies have been identified in skeletal ciliopathies, in which primary cilia (PC) function is disrupted. In human ACH and TD, the impact of FGFR3 mutations on PC in growth plate cartilage remains unknown. Here we showed that in chondrocytes from human (ACH, TD) and mouse Fgfr3Y367C/+ cartilage, the constitutively-active FGFR3 perturbed PC length and the sorting and trafficking of IFT20 to the PC...
October 4, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/29037125/signature-of-genetic-associations-in-oral-cancer
#4
Vishwas Sharma, Amrita Nandan, Amitesh Kumar Sharma, Harpreet Singh, Mausumi Bharadwaj, Dhirendra Narain Sinha, Ravi Mehrotra
Oral cancer etiology is complex and controlled by multi-factorial events including genetic events. Candidate gene studies, genome-wide association studies, and next-generation sequencing identified various chromosomal loci to be associated with oral cancer. There is no available review that could give us the comprehensive picture of genetic loci identified to be associated with oral cancer by candidate gene studies-based, genome-wide association studies-based, and next-generation sequencing-based approaches...
October 2017: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
https://www.readbyqxmd.com/read/29030113/proteomic-analyses-of-signalling-complexes-associated-with-receptor-tyrosine-kinase-identify-novel-members-of-fibroblast-growth-factor-receptor-3-interactome
#5
Lukas Balek, Pavel Nemec, Peter Konik, Michaela Kunova Bosakova, Miroslav Varecha, Iva Gudernova, Jirina Medalova, Deborah Krakow, Pavel Krejci
Receptor tyrosine kinases (RTKs) form multiprotein complexes that initiate and propagate intracellular signals and determine the RTK-specific signalling patterns. Unravelling the full complexity of protein interactions within the RTK-associated complexes is essential for understanding of RTK functions, yet it remains an understudied area of cell biology. We describe a comprehensive approach to characterize RTK interactome. A single tag immunoprecipitation and phosphotyrosine protein isolation followed by mass-spectrometry was used to identify proteins interacting with fibroblast growth factor receptor 3 (FGFR3)...
October 10, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/29026271/acanthosis-nigricans-in-a-japanese-boy-with-hypochondroplasia-due-to-a-k650t-mutation-in-fgfr3
#6
Hiroki Hirai, Junpei Hamada, Kosei Hasegawa, Eiichi Ishii
Acanthosis nigricans (AN) is observed in some cases of skeletal dysplasia. However, AN has occasionally been reported in patients with hypochondroplasia (HCH), and a clinical diagnosis is sometimes difficult when its physical and radiological features are mild. Mutations in the gene encoding the fibroblast growth factor receptor 3 (FGFR3) have been identified as the cause of some types of skeletal dysplasia, which is diagnostically useful. Here, we report the case of a 3-yr-old Japanese boy who presented with AN...
2017: Clinical Pediatric Endocrinology: Case Reports and Clinical Investigations: Official Journal of the Japanese Society for Pediatric Endocrinology
https://www.readbyqxmd.com/read/29025200/novel-genetic-cause-of-idiopathic-short-stature
#7
REVIEW
Min Jae Kang
Traditionally, the growth hormone - insulin-like growth factor I (GH - IGF-I) axis is the most important signaling pathway in linear growth, and defects in this axis present as growth hormone deficiencies or IGF-I deficiencies. However, subtle changes in serum levels of GH or IGF-I, caused by gene mutations involved in the GH - IGF-I axis, can present as idiopathic short stature (ISS). This paper briefly discusses GHR and IGFALS. In addition, recent studies have shown that many factors, including paracrine signals, extracellular matrix, and intracellular mechanisms of chondrocytes, regulate the growth plate independent of the GH - IGF-I system...
September 2017: Annals of Pediatric Endocrinology & Metabolism
https://www.readbyqxmd.com/read/29019756/imaging-of-skeletal-disorders-caused-by-fibroblast-growth-factor-receptor-gene-mutations
#8
Kiran M Sargar, Achint K Singh, Simon C Kao
Fibroblast growth factors and fibroblast growth factor receptors (FGFRs) play important roles in human axial and craniofacial skeletal development. FGFR1, FGFR2, and FGFR3 are crucial for both chondrogenesis and osteogenesis. Mutations in the genes encoding FGFRs, types 1-3, are responsible for various skeletal dysplasias and craniosynostosis syndromes. Many of these disorders are relatively common in the pediatric population, and diagnosis is often challenging. These skeletal disorders can be classified based on which FGFR is affected...
October 2017: Radiographics: a Review Publication of the Radiological Society of North America, Inc
https://www.readbyqxmd.com/read/28980322/fibroblast-growth-factor-21-attenuates-calcification-of-vascular-smooth-muscle-cells-in%C3%A2-vitro
#9
Fangying Cao, Shaoping Wang, Xiangrong Cao, Xiaoxiao Liu, Kun Fu, Peng Hao, Jinghua Liu
OBJECTIVES: Vascular calcification is a dysfunction of the vasculature. Recent findings indicate that fibroblast growth factor21 (FGF21), a protector of the cardiovascular system, is related to the mineral deposition of bone and enhances the osteogenic activity of bone morphogenic protein (BMP)-2. In this study, we explored whether FGF21 suppresses vascular calcification. METHODS: A calcifying model was established by culturing primary rat vascular aortic smooth muscle cells (VSMCs) in a beta-glycerophosphate (BGP)-containing calcifying medium for 14 days...
October 4, 2017: Journal of Pharmacy and Pharmacology
https://www.readbyqxmd.com/read/28976058/diffuse-gliomas-with-fgfr3-tacc3-fusion-have-characteristic-histopathological-and-molecular-features
#10
Franck Bielle, Anna-Luisa Di Stefano, David Meyronnet, Alberto Picca, Chiara Villa, Michèle Bernier, Yohann Schmitt, Marine Giry, Audrey Rousseau, Dominique Figarella-Branger, Claude-Alain Maurage, Emmanuelle Uro-Coste, Anna Lasorella, Antonio Iavarone, Marc Sanson, Karima Mokhtari
Adult glioblastomas, IDH-wildtype represent a heterogeneous group of diseases. They are resistant to conventional treatment by concomitant radiochemotherapy and carry a dismal prognosis. The discovery of oncogenic gene fusions in these tumors has led to prospective targeted treatments, but identification of these rare alterations in practice is challenging. Here, we report a series of 30 adult diffuse gliomas with an in frame FGFR3-TACC3 oncogenic fusion (n=27 WHO grade IV and n=3 WHO grade II) as well as their histological and molecular features...
October 4, 2017: Brain Pathology
https://www.readbyqxmd.com/read/28964968/dephosphorylation-is-the-mechanism-of-fibroblast-growth-factor-inhibition-of-guanylyl-cyclase-b
#11
Jerid W Robinson, Jeremy R Egbert, Julia Davydova, Hannes Schmidt, Laurinda A Jaffe, Lincoln R Potter
Activating mutations in fibroblast growth factor receptor 3 (FGFR3) and inactivating mutations of guanylyl cyclase-B (GC-B, also called NPRB or NPR2) cause dwarfism. FGF exposure inhibits GC-B activity in a chondrocyte cell line, but the mechanism of the inactivation is not known. Here, we report that FGF exposure causes dephosphorylation of GC-B in rat chondrosarcoma cells, which correlates with a rapid, potent and reversible inhibition of C-type natriuretic peptide-dependent activation of GC-B. Cells expressing a phosphomimetic mutant of GC-B that cannot be inactivated by dephosphorylation because it contains glutamate substitutions for all known phosphorylation sites showed no decrease in GC-B activity in response to FGF...
September 28, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28953502/endometrial-cancers-harboring-mutated-fibroblast-growth-factor-receptor-2-protein-are-successfully-treated-with-a-new-small-tyrosine-kinase-inhibitor-in-an-orthotopic-mouse-model
#12
Sebastien Taurin, Chieh-Hsiang Yang, Maria Reyes, Sungpil Cho, Demetrius M Coombs, Elke A Jarboe, Theresa L Werner, C Matthew Peterson, Margit M Janát-Amsbury
OBJECTIVES: AL3818 (anlotinib) is a receptor tyrosine kinase inhibitor targeting vascular endothelial growth factor receptors (VEGFR1, VEGFR2/KDR, and VEGFR3), stem cell factor receptor (C-kit), platelet-derived growth factor (PDGFβ), and fibroblast growth factor receptors (FGFR1, FGFR2, and FGFR3). This study evaluates the efficacy of AL3818 studying tumor regression in an orthotopic murine endometrial cancer model. METHODS: We tested the cytotoxicity of AL3818 on a panel of 7 human endometrial cancer cell lines expressing either wild-type or mutant FGFR2 and also assessed the in vivo antitumor efficacy in a murine, orthotopic AN3CA endometrial cancer model...
September 26, 2017: International Journal of Gynecological Cancer
https://www.readbyqxmd.com/read/28927152/expression-levels-of-fgfr3-as-a-prognostic-marker-for-the-progression-of-primary-pt1-bladder-cancer-and-its-association-with-mutation-status
#13
Ho Won Kang, Ye-Hwan Kim, Pildu Jeong, Cheol Park, Won Tae Kim, Dong Hee Ryu, Eun-Jong Cha, Yun-Sok Ha, Tae-Hwan Kim, Tae Gyun Kwon, Sung-Kwon Moon, Yung Hyun Choi, Seok-Joong Yun, Wun-Jae Kim
The present study examined the utility of fibroblast growth factor receptor 3 (FGFR3) mutation status and gene expression as a prognostic marker in primary pT1 bladder cancer (BC). A total of 120 patients with primary pT1 BC were enrolled. FGFR3 mutation status was determined by direct sequencing and FGFR3 mRNA expression level was determined by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analysis. The results were compared with the clinicopathological parameters, and the prognostic value of FGFR3 was evaluated by Kaplan-Meier analysis and a multivariate Cox regression test...
September 2017: Oncology Letters
https://www.readbyqxmd.com/read/28924384/fgfr3-deficient-mice-have-accelerated-fracture-repair
#14
Yangli Xie, Fengtao Luo, Wei Xu, Zuqiang Wang, Xianding Sun, Meng Xu, Junlan Huang, Dali Zhang, Qiaoyan Tan, Bo Chen, Wanling Jiang, Xiaolan Du, Lin Chen
Bone fracture healing is processed through multiple biological stages that partly recapitulates the skeletal development process. FGFR3 is a negative regulator of chondrogenesis during embryonic stage and plays an important role in both chondrogenesis and osteogenesis. We have investigated the role of FGFR3 in fracture healing using unstabilized fracture model and found that gain-of-function mutation of FGFR3 inhibits the initiation of chondrogenesis during cartilage callus formation. Here, we created closed, stabilized proximal tibia fractures with an intramedullary pin in Fgfr3(-/-)mice and their littermate wild-type mice...
2017: International Journal of Biological Sciences
https://www.readbyqxmd.com/read/28912571/comparative-global-immune-related-gene-profiling-of-somatic-cells-human-pluripotent-stem-cells-and-their-derivatives-implication-for-human-lymphocyte-proliferation
#15
Chia-Eng Wu, Chen-Wei Yu, Kai-Wei Chang, Wen-Hsi Chou, Chen-Yu Lu, Elisa Ghelfi, Fang-Chun Wu, Pey-Shynan Jan, Mei-Chi Huang, Patrick Allard, Shau-Ping Lin, Hong-Nerng Ho, Hsin-Fu Chen
Human pluripotent stem cells (hPSCs), including embryonic stem cells (ESCs) and induced PSCs (iPSCs), represent potentially unlimited cell sources for clinical applications. Previous studies have suggested that hPSCs may benefit from immune privilege and limited immunogenicity, as reflected by the reduced expression of major histocompatibility complex class-related molecules. Here we investigated the global immune-related gene expression profiles of human ESCs, hiPSCs and somatic cells and identified candidate immune-related genes that may alter their immunogenicity...
September 15, 2017: Experimental & Molecular Medicine
https://www.readbyqxmd.com/read/28912153/comprehensive-genomic-profiling-of-282-pediatric-low-and-high-grade-gliomas-reveals-genomic-drivers-tumor-mutational-burden-and-hypermutation-signatures
#16
Adrienne Johnson, Eric Severson, Laurie Gay, Jo-Anne Vergilio, Julia Elvin, James Suh, Sugganth Daniel, Mandy Covert, Garrett M Frampton, Sigmund Hsu, Glenn J Lesser, Kimberly Stogner-Underwood, Ryan T Mott, Sarah Z Rush, Jennifer J Stanke, Sonika Dahiya, James Sun, Prasanth Reddy, Zachary R Chalmers, Rachel Erlich, Yakov Chudnovsky, David Fabrizio, Alexa B Schrock, Siraj Ali, Vincent Miller, Philip J Stephens, Jeffrey Ross, John R Crawford, Shakti H Ramkissoon
BACKGROUND: Pediatric brain tumors are the leading cause of death for children with cancer in the U.S. Incorporating next-generation sequencing data for both pediatric low-grade (pLGGs) and high-grade gliomas (pHGGs) can inform diagnostic, prognostic, and therapeutic decision-making. MATERIALS AND METHODS: We performed comprehensive genomic profiling on 282 pediatric gliomas (157 pHGGs, 125 pLGGs), sequencing 315 cancer-related genes and calculating the tumor mutational burden (TMB; mutations per megabase [Mb])...
September 14, 2017: Oncologist
https://www.readbyqxmd.com/read/28911208/hdac6-deficiency-or-inhibition-blocks-fgfr3-accumulation-and-improves-bone-growth-in-a-model-of-achondroplasia
#17
Sara Ota, Zi-Qiang Zhou, Megan P Romero, Guang Yang, Peter J Hurlin
No abstract text is available yet for this article.
September 15, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28905937/somcl-085-a-novel-multi-targeted-fgfr-inhibitor-displays-potent-anticancer-activity-in-fgfr-addicted-human-cancer-models
#18
Xi-Fei Jiang, Yang Dai, Xia Peng, Yan-Yan Shen, Yi Su, Man-Man Wei, Wei-Ren Liu, Zhen-Bin Ding, Ao Zhang, Ying-Hong Shi, Jing Ai
Aberrant fibroblast growth factor receptor (FGFR) activation is found across a diverse spectrum of malignancies, especially those lacking effective treatments. SOMCL-085 is a novel FGFR-dominant multi-target kinase inhibitor. Here, we explored the FGFR-targeting anticancer activity of SOMCL-085 both in vitro and in vivo. Among a panel of 20 tyrosine kinases screened, SOMCL-085 potently inhibited FGFR1, FGFR2 and FGFR3 kinase activity, with IC50 values of 1.8, 1.9 and 6.9 nmol/L, respectively. This compound simultaneously inhibited the angiogenesis kinases VEGFR and PDGFR, but without obvious inhibitory effect on other 12 tyrosine kinases...
September 14, 2017: Acta Pharmacologica Sinica
https://www.readbyqxmd.com/read/28870692/distinct-patterns-of-acral-melanoma-based-on-site-and-relative-sun-exposure
#19
Alexandra M Haugh, Bin Zhang, Victor L Quan, Erin M Garfield, Jeffrey A Bubley, Emily Kudalkar, Anna Elisa Verzi, Kara Walton, Timothy VandenBoom, Emily A Merkel, Christina Y Lee, Timothy Tan, Maria Cristina Isales, Betty Y Kong, Alexander T Wenzel, Christopher G Bunick, Jaehyuk Choi, Jeffrey Sosman, Pedram Gerami
Acral melanoma is distinct from melanoma of other cutaneous sites, yet there is considerable variation within this category. To better define this variation, we assessed melanomas occurring on dorsal (n=21), volar (n=9), and subungual/interdigital (n=13) acral skin as well as acral nevi (n=24) for clinical, histologic, and molecular features. Melanomas on dorsal acral surfaces demonstrated clear differences compared to volar and subungual/interdigital melanomas. The latter two groups exhibited significantly less frequent BRAF mutations (p=...
September 1, 2017: Journal of Investigative Dermatology
https://www.readbyqxmd.com/read/28855393/fgfr3-tacc3-cancer-gene-fusions-cause-mitotic-defects-by-removal-of-endogenous-tacc3-from-the-mitotic-spindle
#20
Sourav Sarkar, Ellis L Ryan, Stephen J Royle
Fibroblast growth factor receptor 3-transforming acidic coiled-coil containing protein 3 (FGFR3-TACC3; FT3) is a gene fusion resulting from rearrangement of chromosome 4 that has been identified in many cancers including those of the urinary bladder. Altered FGFR3 signalling in FT3-positive cells is thought to contribute to cancer progression. However, potential changes in TACC3 function in these cells have not been explored. TACC3 is a mitotic spindle protein required for accurate chromosome segregation. Errors in segregation lead to aneuploidy, which can contribute to cancer progression...
August 2017: Open Biology
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