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Annekathrin Reinhardt, Damian Stichel, Daniel Schrimpf, Felix Sahm, Andrey Korshunov, David E Reuss, Christian Koelsche, Kristin Huang, Annika K Wefers, Volker Hovestadt, Martin Sill, Dorothee Gramatzki, Joerg Felsberg, Guido Reifenberger, Arend Koch, Ulrich-W Thomale, Albert Becker, Volkmar H Hans, Marco Prinz, Ori Staszewski, Till Acker, Hildegard Dohmen, Christian Hartmann, Wolf Mueller, Muin S A Tuffaha, Werner Paulus, Katharina Heß, Benjamin Brokinkel, Jens Schittenhelm, Camelia-Maria Monoranu, Almuth Friederike Kessler, Mario Loehr, Rolf Buslei, Martina Deckert, Christian Mawrin, Patricia Kohlhof, Ekkehard Hewer, Adriana Olar, Fausto J Rodriguez, Caterina Giannini, Amulya A NageswaraRao, Uri Tabori, Nuno Miguel Nunes, Michael Weller, Ute Pohl, Zane Jaunmuktane, Sebastian Brandner, Andreas Unterberg, Daniel Hänggi, Michael Platten, Stefan M Pfister, Wolfgang Wick, Christel Herold-Mende, David T W Jones, Andreas von Deimling, David Capper
Tumors with histological features of pilocytic astrocytoma (PA), but with increased mitotic activity and additional high-grade features (particularly microvascular proliferation and palisading necrosis) have often been designated anaplastic pilocytic astrocytomas. The status of these tumors as a separate entity has not yet been conclusively demonstrated and molecular features have only been partially characterized. We performed DNA methylation profiling of 102 histologically defined anaplastic pilocytic astrocytomas...
March 21, 2018: Acta Neuropathologica
Alan Jiang, Qiufeng Liu, Ruifeng Wang, Peng Wei, Yang Dai, Xin Wang, Yechun Xu, Yuchi Ma, Jing Ai, Jingkang Shen, Jian Ding, Bing Xiong
Fibroblast growth factor receptors (FGFRs), a subfamily of receptor tyrosine kinases, are aberrant in various cancer types, and considered to be promising targets for cancer therapy. We started with a weak-active compound that was identified from our internal hepatocyte growth factor receptor (also called c-Met) inhibitor project, and optimized it with the guidance of a co-crystal structure of compound 8 with FGFR1. Through rational design, synthesis, and the biological evaluation of a series of 5 H -pyrrolo[2,3- b ]pyrazine derivatives, we discovered several potent FGFR kinase inhibitors...
March 19, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Y Jiang, H Y Chao, X W Zhang, M Zhou, X Z Lu, R Zhang, C He, Q Wang
Objective: To explore the effects and possible mechanisms of the novel pan-FGFR inhibitor BGJ398 on KG-1 cells in vitro. Methods: Effects of BGJ398 on cells proliferation were detected by CCK-8, the apoptosis was assessed by Annexin V-FITC. Reverse transcriptionquantitative polymerase chain reaction (q-PCR) analysis was used to detect the expression of apoptosis-related genes B cell lymphoma-2 (Bcl-2) and caspase-3. Western blotting analysis was performed to explore the proteins expression levels of Bcl-2, caspase-3 and the expression of p-AKT, p-S6K, p-ERK and FGFR1...
February 14, 2018: Zhonghua Xue Ye Xue za Zhi, Zhonghua Xueyexue Zazhi
Despina Apostolopoulou, Olga S Kaxira, Angeliki Hatzaki, Kanaris P Panagopoulos, Konstantinos Alexandrou, Alexander Stratoudakis, Panagoula Kollia, Vassiliki Aleporou
INTRODUCTION: Craniosynostosis, the premature fusion of cranial sutures, is usually divided into 2 major categories: syndromic and nonsyndromic. Mutations in the FGFR1, FGFR2, FGFR3, TWIST1, and EFNB1 genes cause the common craniosynostosis syndromes Muenke, Crouzon and Crouzon with acanthosis nigricans, Apert, Pfeiffer, Saethre-Chotzen, and Craniofrontonasal. Overlapping features among craniosynostosis syndromes, phenotypic heterogeneity even within the same syndrome, especially in the case of Muenke syndrome, and inadequate clinical evaluation can lead to misdiagnosis, which molecular testing can help clarify...
January 1, 2018: Cleft Palate-craniofacial Journal
Vanessa Benham, Debrup Chakraborty, Blair Bullard, Jamie J Bernard
Obesity is a leading risk factor for post-menopausal breast cancer, and this is concerning as 40% of cancer diagnoses in 2014 were associated with overweight/obesity. Despite this epidemiological link, the underlying mechanism responsible is unknown. We recently published that visceral adipose tissue (VAT) releases FGF2 and stimulates the transformation of skin epithelial cells. Furthermore, obesity is differentially associated with many epithelial cancers, and this mechanistic link could be translational. As FGF2 and FGFR1 are implicated in breast cancer progression, we hypothesize that VAT-derived FGF2 plays a translational role in promoting adiposity-associated mammary epithelial cell transformation...
March 21, 2018: Adipocyte
Keith G Avin, Julian A Vallejo, Neal X Chen, Kun Wang, Chad D Touchberry, Marco Brotto, Sarah L Dallas, Sharon M Moe, Michael J Wacker
Skeletal muscle dysfunction accompanies the clinical disorders of chronic kidney disease (CKD) and hereditary hypophosphatemic rickets. In both disorders fibroblast growth factor 23 (FGF23), a bone-derived hormone regulating phosphate and vitamin D metabolism, becomes chronically elevated. FGF23 has been shown to play a direct role in cardiac muscle dysfunction; however, it is unknown whether FGF23 signaling can also directly induce skeletal muscle dysfunction. We found expression of potential FGF23 receptors ( Fgfr1-4) and α-Klotho in muscles of two animal models (CD-1 and Cy/+ rat, a naturally occurring rat model of Chronic Kidney Disease-Mineral Bone Disorder) as well as C2 C12 myoblasts and myotubes...
March 20, 2018: American Journal of Physiology. Endocrinology and Metabolism
Soonchan Park, Miji Lee, Kyung-Ja Cho, Sung Bae Kim, Jong-Lyel Roh, Seung-Ho Choi, Soon Yuhl Nam, Sang Yoon Kim, Joon Seon Song
Amplification of fibroblast growth factor receptor 1 ( FGFR1) has been reported in many squamous cell carcinomas, and human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma has been characterized as a distinct subset with favorable prognosis. Here, we investigated the FGFR1 amplification and HPV status in tonsillar squamous cell carcinoma (TSCC) and analyzed the clinical characteristics. HPV in situ hybridization (HPV ISH) and FGFR1 fluorescence in situ hybridization (FISH) were performed using tissue microarray from 89 cases of TSCC...
March 1, 2018: Journal of Histochemistry and Cytochemistry: Official Journal of the Histochemistry Society
Vincent Plagnol, Samuel Woodhouse, Karen Howarth, Stefanie Lensing, Matt Smith, Michael Epstein, Mikidache Madi, Sarah Smalley, Catherine Leroy, Jonathan Hinton, Frank de Kievit, Esther Musgrave-Brown, Colin Herd, Katherine Baker-Neblett, Will Brennan, Peter Dimitrov, Nathan Campbell, Clive Morris, Nitzan Rosenfeld, James Clark, Davina Gale, Jamie Platt, John Calaway, Greg Jones, Tim Forshew
Circulating tumor DNA (ctDNA) analysis is being incorporated into cancer care; notably in profiling patients to guide treatment decisions. Responses to targeted therapies have been observed in patients with actionable mutations detected in plasma DNA at variant allele fractions (VAFs) below 0.5%. Highly sensitive methods are therefore required for optimal clinical use. To enable objective assessment of assay performance, detailed analytical validation is required. We developed the InVisionFirst™ assay, an assay based on enhanced tagged amplicon sequencing (eTAm-Seq™) technology to profile 36 genes commonly mutated in non-small cell lung cancer (NSCLC) and other cancer types for actionable genomic alterations in cell-free DNA...
2018: PloS One
Caterina Fumagalli, Davide Vacirca, Alessandra Rappa, Antonio Passaro, Juliana Guarize, Paola Rafaniello Raviele, Filippo de Marinis, Lorenzo Spaggiari, Chiara Casadio, Giuseppe Viale, Massimo Barberis, Elena Guerini-Rocco
BACKGROUND: Molecular profiling of advanced non-small cell lung cancers (NSCLC) is essential to identify patients who may benefit from targeted treatments. In the last years, the number of potentially actionable molecular alterations has rapidly increased. Next-generation sequencing allows for the analysis of multiple genes simultaneously. AIMS: To evaluate the feasibility and the throughput of next-generation sequencing in clinical molecular diagnostics of advanced NSCLC...
March 13, 2018: Journal of Clinical Pathology
Yuming Wang, Lijun Li, Jun Fan, Yang Dai, Alan Jiang, Mei-Yu Geng, Jing Ai, Wenhu Duan
Fibroblast growth factor receptors (FGFR1-4) are promising therapeutic targets in many cancers. With the resurgence of interest in irreversible inhibitors, efforts have been directed to the discovery of irreversible FGFR inhibitors. Currently, several selective irreversible inhibitors are being evaluated in clinical trials that could covalently target a conserved cysteine in the P-loop of FGFR. In this article, we used a structure-guided approach that is rationalized by a computer-aided simulation to discover the novel and irreversible pan-FGFR inhibitor, 9g, which provided superior FGFR in vitro activities and decent selectivity over VEGFR2 (vascular endothelia growth factor receptor 2)...
March 9, 2018: Journal of Medicinal Chemistry
José E Velázquez Vega, Daniel J Brat
Recent advances in molecular pathology have reshaped the practice of brain tumor diagnostics. The classification of gliomas has been restructured with the discovery of isocitrate dehydrogenase (IDH) 1/2 mutations in the vast majority of lower grade infiltrating gliomas and secondary glioblastomas (GBM), with IDH-mutant astrocytomas further characterized by TP53 and ATRX mutations. Whole-arm 1p/19q codeletion in conjunction with IDH mutations now define oligodendrogliomas, which are also enriched for CIC, FUBP1, PI3K, NOTCH1, and TERT-p mutations...
March 8, 2018: Advances in Anatomic Pathology
Hong Luo, Jin Quan, He Xiao, Jia Luo, Qin Zhang, Guocheng Pi, Yunfei Ye, Rong He, Yun Liu, Xiaona Su, Lianhua Zhao, Ge Wang
Activation of fibroblast growth factor receptor (FGFR) signaling occurs in various cancers, including esophageal squamous cell carcinoma (ESCC), however, the effect of targeting FGFR in ESCC is not clear. Herein, we examined the phosphorylation level of FGFR1Y654 (p‑FGFR1) in ESCC cell lines and tumor tissues, as well as the cancer cell killing effects of gefitinib and FGFR inhibitor AZD4547 in combination form or alone in ESCC cells. Immunohistochemistry staining was used to detect the expression level of p‑FGFR1 in 87 ESCC specimens...
March 8, 2018: Oncology Reports
Silvia Martina Ferrari, Guido Bocci, Teresa Di Desidero, Giusy Elia, Ilaria Ruffilli, Francesca Ragusa, Paola Orlandi, Sabrina Rosaria Paparo, Armando Patrizio, Simona Piaggi, Concettina La Motta, Salvatore Ulisse, Enke Baldini, Gabriele Materazzi, Paolo Miccoli, Alessandro Antonelli, Poupak Fallahi
Lenvatinib is an oral, multitargeted tyrosine kinase inhibitor (TKI) of VEGFR1-VEGFR3, FGFR1-FGFR4, PDGFRα, RET and v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) signaling networks involved in tumor angiogenesis. We have evaluated the antitumor activity of lenvatinib in primary anaplastic thyroid cancer (ATC) cells, in the human cell line 8305C (undifferentiated thyroid cancer) and in an ATC-cell line (AF). The AF cell line was obtained from the primary ATC cultures and was the one that grew over 50 passages...
March 8, 2018: Oncology Reports
Kimberley N Sent-Doux, Craig Mackinnon, Jen-Chieh Lee, Andrew L Folpe, Omar Habeeb
Phosphaturic Mesenchymal Tumor (PMT) is a rare, histologically distinctive neoplasm, which classically presents with phosphaturia and tumor-induced osteomalacia (TIO) (i.e., oncogenic osteomalacia). Both the phosphaturia and TIO are due to paraneoplastic production of FGF23 (a phosphatonin) by the neoplastic cells, which are genetically characterized by rearrangements of FN1 (most often with FGFR1 - and less frequently with FGF1). However, rare cases of PMT present without phosphaturia and TIO (i.e., the "non-phosphaturic" variant) - and are therefore much more challenging to diagnose...
March 4, 2018: Human Pathology
Caio H Mazucanti, Elisa M Kawamoto, Mark P Mattson, Cristoforo Scavone, Simonetta Camandola
Mutations of the β-glucuronidase protein α-Klotho have been associated with premature aging, and altered cognitive function. Although highly expressed in specific areas of the brain, Klotho functions in the central nervous system remain unknown. Here, we show that cultured hippocampal neurons respond to insulin and glutamate stimulation by elevating Klotho protein levels. Conversely, AMPA and NMDA antagonism suppress neuronal Klotho expression. We also provide evidence that soluble Klotho enhances astrocytic aerobic glycolysis by hindering pyruvate metabolism through the mitochondria, and stimulating its processing by lactate dehydrogenase...
January 1, 2018: Journal of Cerebral Blood Flow and Metabolism
Sadakatsu Ikeda, Igor F Tsigelny, Åge A Skjevik, Yuko Kono, Michel Mendler, Alexander Kuo, Jason K Sicklick, Gregory Heestand, Kimberly C Banks, AmirAli Talasaz, Richard B Lanman, Scott Lippman, Razelle Kurzrock
BACKGROUND: Because imaging has a high sensitivity to diagnose hepatocellular carcinoma (HCC) and tissue biopsies carry risks such as bleeding, the latter are often not performed in HCC. Blood-derived circulating tumor DNA (ctDNA) analysis can identify somatic alterations, but its utility has not been characterized in HCC. MATERIALS AND METHODS: We evaluated 14 patients with advanced HCC (digital ctDNA sequencing [68 genes]). Mutant relative to wild-type allele fraction was calculated...
February 27, 2018: Oncologist
Kento Umino, Shin-Ichiro Fujiwara, Takashi Ikeda, Yumiko Toda, Shoko Ito, Kiyomi Mashima, Daisuke Minakata, Hirofumi Nakano, Ryoko Yamasaki, Yasufumi Kawasaki, Miyuki Sugimoto, Chihiro Yamamoto, Masahiro Ashizawa, Kaoru Hatano, Kazuya Sato, Iekuni Oh, Ken Ohmine, Kazuo Muroi, Yoshinobu Kanda
OBJECTIVE: Myeloid/lymphoid neoplasms with fibroblast growth factor receptor-1 (FGFR1) rearrangement are hematopoietic stem cell disorders with a poor prognosis, but no established standard therapy. METHODS: We experienced a patient with T-lymphoblastic lymphoma (LBL) associated with FGFR1 rearrangement who underwent cord blood transplantation, but died of pulmonary complication. We collected the clinical data of patients with FGFR1 rearrangement from the medical literature and analyzed 45 patients, including our patient...
February 28, 2018: Hematology (Amsterdam, Netherlands)
Ganesh Pathare, Manuel Anderegg, Giuseppe Albano, Florian Lang, Daniel G Fuster
Fibroblast growth factor 23 (FGF23) participates in the orchestration of mineral metabolism by inducing phosphaturia and decreasing the production of 1,25(OH)2 D3 . It is known that FGF23 release is stimulated by aldosterone and extracellular volume depletion. To characterize this effect further in a model of mild hypovolemia, we studied mice lacking the thiazide sensitive NaCl cotransporter (NCC). Our data indicate that NCC knockout mice (KO) have significantly higher FGF23, PTH and aldosterone concentrations than corresponding wild type (WT) mice...
February 26, 2018: Scientific Reports
Yu-Chen Shi, Wei-Wei Lu, Yue-Long Hou, Kun Fu, Feng Gan, Shu-Juan Cheng, Shao-Ping Wang, Yong-Fen Qi, Jing-Hua Liu
Background: Chronic kidney disease (CKD) is closely related to the cardiovascular events in vascular calcification (VC). However, little has known about the characteristics of kidney injury caused by VC. Fibroblast growth factor 21 (FGF21) is an endocrine factor, which takes part in various metabolic actions with the potential to alleviate metabolic disorder diseases. Even FGF21 has been regarded as a biomarker in CKD, the role of FGF21 in CKD remains unclear. Therefore, in this study, we evaluate the FGF21 on the kidney injury in VC rats...
March 5, 2018: Chinese Medical Journal
Marc Diedisheim, Masaya Oshima, Olivier Albagli, Charlotte Wennberg Huldt, Ingela Ahlstedt, Maryam Clausen, Suraj Menon, Alexander Aivazidis, Anne-Christine Andreasson, William G Haynes, Piero Marchetti, Lorella Marselli, Mathieu Armanet, Fabrice Chimienti, Raphael Scharfmann
OBJECTIVE: Dedifferentiation could explain reduced functional pancreatic β-cell mass in type 2 diabetes (T2D). METHODS: Here we model human β-cell dedifferentiation using growth factor stimulation in the human β-cell line, EndoC-βH1, and human pancreatic islets. RESULTS: Fibroblast growth factor 2 (FGF2) treatment reduced expression of β-cell markers, (INS, MAFB, SLC2A2, SLC30A8, and GCK) and activated ectopic expression of MYC, HES1, SOX9, and NEUROG3...
February 8, 2018: Molecular Metabolism
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