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https://www.readbyqxmd.com/read/29312610/inhibitor-repurposing-reveals-alk-ltk-fgfr-ret-and-trk-kinases-as-the-targets-of-azd1480
#1
Iva Gudernova, Lukas Balek, Miroslav Varecha, Jana Fialova Kucerova, Michaela Kunova Bosakova, Bohumil Fafilek, Veronika Palusova, Stjepan Uldrijan, Lukas Trantirek, Pavel Krejci
Many tyrosine kinase inhibitors (TKIs) have failed to reach human use due to insufficient activity in clinical trials. However, the failed TKIs may still benefit patients if their other kinase targets are identified by providing treatment focused on syndromes driven by these kinases. Here, we searched for novel targets of AZD1480, an inhibitor of JAK2 kinase that recently failed phase two cancer clinical trials due to a lack of activity. Twenty seven human receptor tyrosine kinases (RTKs) and 153 of their disease-associated mutants were in-cell profiled for activity in the presence of AZD1480 using a newly developed RTK plasmid library...
December 12, 2017: Oncotarget
https://www.readbyqxmd.com/read/29305654/spontaneous-regression-of-neuroblastoma
#2
REVIEW
Garrett M Brodeur
Neuroblastomas are characterized by heterogeneous clinical behavior, from spontaneous regression or differentiation into a benign ganglioneuroma, to relentless progression despite aggressive, multimodality therapy. Indeed, neuroblastoma is unique among human cancers in terms of its propensity to undergo spontaneous regression. The strongest evidence for this comes from the mass screening studies conducted in Japan, North America and Europe and it is most evident in infants with stage 4S disease. This propensity is associated with a pattern of genomic change characterized by whole chromosome gains rather than segmental chromosome changes but the mechanism(s) underlying spontaneous regression are currently a matter of speculation...
January 5, 2018: Cell and Tissue Research
https://www.readbyqxmd.com/read/29249692/%C3%AE-2-adrenergic-neurotrophin-feedforward-loop-promotes-pancreatic-cancer
#3
Bernhard W Renz, Ryota Takahashi, Takayuki Tanaka, Marina Macchini, Yoku Hayakawa, Zahra Dantes, H Carlo Maurer, Xiaowei Chen, Zhengyu Jiang, C Benedikt Westphalen, Matthias Ilmer, Giovanni Valenti, Sarajo K Mohanta, Andreas J R Habenicht, Moritz Middelhoff, Timothy Chu, Karan Nagar, Yagnesh Tailor, Riccardo Casadei, Mariacristina Di Marco, Axel Kleespies, Richard A Friedman, Helen Remotti, Maximilian Reichert, Daniel L Worthley, Jens Neumann, Jens Werner, Alina C Iuga, Kenneth P Olive, Timothy C Wang
Catecholamines stimulate epithelial proliferation, but the role of sympathetic nerve signaling in pancreatic ductal adenocarcinoma (PDAC) is poorly understood. Catecholamines promoted ADRB2-dependent PDAC development, nerve growth factor (NGF) secretion, and pancreatic nerve density. Pancreatic Ngf overexpression accelerated tumor development in LSL-Kras+/G12D;Pdx1-Cre (KC) mice. ADRB2 blockade together with gemcitabine reduced NGF expression and nerve density, and increased survival of LSL-Kras+/G12D;LSL-Trp53+/R172H;Pdx1-Cre (KPC) mice...
December 1, 2017: Cancer Cell
https://www.readbyqxmd.com/read/29247376/neurotrophin-expression-in-lymphocytes-a-powerful-indicator-of-degeneration-in-parkinson-s-disease-amyotrophic-lateral-sclerosis-and-ataxia
#4
Anjana Sadanand, Anjali Janardhanan, A J Vanisree, Thamil Pavai
Deregulated neurotrophin is an etiological factor in the pathology of neurodegenerative diseases (ND) that are clinically different entities but characterised by similar limb dysfunction. Earlier validation of peripheral biomarkers can provide significant translational benefit to ND patients. We analysed brain-derived neurotrophic factor (BDNF)-tropomyosin possessing tyrosine-related kinase (Trk B) and its key downstream proteins which are implicated in ND such as Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and ataxia...
December 16, 2017: Journal of Molecular Neuroscience: MN
https://www.readbyqxmd.com/read/29237803/anti-tumor-activity-of-entrectinib-a-pan-trk-ros1-and-alk-inhibitor-in-etv6-ntrk3-positive-acute-myeloid-leukemia
#5
Kristen M Smith, Patrick C Fagan, Elena Pomari, Giuseppe Germano, Chiara Frasson, Colin Walsh, Ian M Silverman, Paolo Bonvini, Gang Li
Activation of tropomyosin receptor kinase (TRK) family tyrosine kinases by chromosomal rearrangement has been shown to drive a wide range of solid tumors and hematologic malignancies. TRK fusions are actionable targets as evidenced by recent clinical trial results in solid tumors. Entrectinib (RXDX-101) is an investigational, orally available, CNS-active, highly potent and selective kinase inhibitor against TRKA/B/C, ROS1 and ALK kinase activities. Here, we demonstrate that TRK kinase inhibition by entrectinib selectively targets preclinical models of TRK fusion-driven hematologic malignancies...
December 13, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29228842/mammary-analogue-secretory-carcinoma-of-the-thyroid-mimicking-locally-advanced-papillary-thyroid-carcinoma-a-rare-case-report
#6
Haihui Liao, Ashraf Khan, Patricia M Miron, Kristine M Cornejo
Mammary analogue secretory carcinoma (MASC) harboring ETV6 gene rearrangements was first described in the salivary gland with a relatively favorable prognosis and a possible molecular therapeutic target with pan-Trk inhibitors. Recently, primary MASC of the thyroid gland has been reported. We report a case of a 4.0 cm MASC arising from the left thyroid of a 58-year-old female with extrathyroidal extension. Initially, it was diagnosed by fine needle aspiration as suspicious for papillary thyroid carcinoma (PTC) and subsequently called a poorly differentiated carcinoma on resection...
December 1, 2017: International Journal of Surgical Pathology
https://www.readbyqxmd.com/read/29222974/cold-atmospheric-plasma-cap-a-novel-physicochemical-source-induces-neural-differentiation-through-cross-talk-between-the-specific-rons-cascade-and-trk-ras-erk-signaling-pathway
#7
Ja-Young Jang, Young June Hong, Junsup Lim, Jin Sung Choi, Eun Ha Choi, Seongman Kang, Hyangshuk Rhim
Plasma, formed by ionization of gas molecules or atoms, is the most abundant form of matter and consists of highly reactive physicochemical species. In the physics and chemistry fields, plasma has been extensively studied; however, the exact action mechanisms of plasma on biological systems, including cells and humans, are not well known. Recent evidence suggests that cold atmospheric plasma (CAP), which refers to plasma used in the biomedical field, may regulate diverse cellular processes, including neural differentiation...
November 30, 2017: Biomaterials
https://www.readbyqxmd.com/read/29222769/neurotrophic-factors-an-overview
#8
Stephen D Skaper
The neurotrophins are a family of closely related proteins that were first identified as survival factors for sympathetic and sensory neurons and have since been shown to control a number of aspects of survival, development, and function of neurons in both the central and peripheral nervous systems. Limiting quantities of neurotrophins during development control the numbers of surviving neurons to ensure a match between neurons and the requirement for a suitable density of target innervation. Biological effects of each of the four mammalian neurotrophins are mediated through activation of one or more of the three members of the tropomyosin-related kinase (Trk) family of receptor tyrosine kinases (TrkA, TrkB, and TrkC)...
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/29215199/neurotrophically-induced-mesenchymal-progenitor-cells-derived-from-induced-pluripotent-stem-cells-enhance-neuritogenesis-via-neurotrophin-and-cytokine-production
#9
Rachel M Brick, Aaron X Sun, Rocky S Tuan
Adult tissue-derived mesenchymal stem cells (MSCs) are known to produce a number of bioactive factors, including neurotrophic growth factors, capable of supporting and improving nerve regeneration. However, with a finite culture expansion capacity, MSCs are inherently limited in their lifespan and use. We examined here the potential utility of an alternative, mesenchymal-like cell source, derived from induced pluripotent stem cells, termed induced mesenchymal progenitor cells (MiMPCs). We found that several genes were upregulated and proteins were produced in MiMPCs that matched those previously reported for MSCs...
January 2018: Stem Cells Translational Medicine
https://www.readbyqxmd.com/read/29215016/low-neurotrophin-receptor-cd271-regulates-phenotype-switching-in-melanoma
#10
Gaetana Restivo, Johanna Diener, Phil F Cheng, Gregor Kiowski, Mario Bonalli, Thomas Biedermann, Ernst Reichmann, Mitchell P Levesque, Reinhard Dummer, Lukas Sommer
Cutaneous melanoma represents the most fatal skin cancer due to its high metastatic capacity. According to the "phenotype switching" model, the aggressive nature of melanoma cells results from their intrinsic potential to dynamically switch from a high-proliferative/low-invasive to a low-proliferative/high-invasive state. Here we identify the low affinity neurotrophin receptor CD271 as a key effector of phenotype switching in melanoma. CD271 plays a dual role in this process by decreasing proliferation, while simultaneously promoting invasiveness...
December 7, 2017: Nature Communications
https://www.readbyqxmd.com/read/29214440/massarray-based-simultaneous-detection-of-hotspot-somatic-mutations-and-recurrent-fusion-genes-in-papillary-thyroid-carcinoma-the-ptc-ma-assay
#11
Chiara Pesenti, Marina Muzza, Carla Colombo, Maria Carla Proverbio, Claudia Farè, Stefano Ferrero, Monica Miozzo, Laura Fugazzola, Silvia Tabano
PURPOSE: We exploited the MassARRAY (MA) genotyping platform to develop the "PTC-MA assay", which allows the simultaneous detection of 13 hotspot mutations, in the BRAF, KRAS, NRAS, HRAS, TERT, AKT1, PIK3CA, and EIF1AX genes, and six recurrent genetic rearrangements, involving the RET and TRK genes in papillary thyroid cancer (PTC). METHODS: The assay was developed using DNA and cDNA from 12 frozen and 11 formalin-fixed paraffin embedded samples from 23 PTC cases, together with positive and negative controls...
December 6, 2017: Endocrine
https://www.readbyqxmd.com/read/29178434/demonstration-of-an-anti-hyperalgesic-effect-of-a-novel-pan-trk-inhibitor-pf-06273340-in-a-battery-of-human-evoked-pain-models
#12
Peter Loudon, Pieter Siebenga, Donal Gorman, Katrina Gore, Pinky Dua, Guido van Amerongen, Justin L Hay, Geert Jan Groeneveld, Richard P Butt
AIM(S): Inhibitors of nerve growth factor (NGF) reduce pain in several chronic pain indications. NGF signals through tyrosine kinase receptors of the tropomyosin-related kinase (Trk) family and the unrelated p75 receptor. PF-06273340 is a small molecule inhibitor of Trks A, B and C that reduces pain in nonclinical models and this study aimed to investigate the pharmacodynamics of this first in class molecule in humans. METHODS: A randomized, double blind, single dose, placebo and active-controlled 5 period cross-over study was conducted in healthy human subjects (NCT02260947)...
November 27, 2017: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/29118225/activity-of-entrectinib-in-a-patient-with-the-first-reported-ntrk-fusion-in-neuroendocrine-cancer
#13
Darren Sigal, Marie Tartar, Marin Xavier, Fei Bao, Patrick Foley, David Luo, Jason Christiansen, Zachary Hornby, Edna Chow Maneval, Pratik Multani
Despite advances in genomic analysis, the molecular origin of neuroendocrine tumors (NETs) is complex and poorly explained by described oncogenes. The neurotrophic TRK family, including NTRK1, 2, and 3, encode the proteins TRKA, TRKB, TRKC, respectively, involved in normal nerve development. Because NETs develop from the diffuse neuroendocrine system, we sought to determine whether NTRK alterations occur in NETs and whether TRK-targeted therapy would be effective. A patient with metastatic well-differentiated NET, likely of the small intestine, was enrolled on the STARTRK2 trial (ClinicalTrials...
November 2017: Journal of the National Comprehensive Cancer Network: JNCCN
https://www.readbyqxmd.com/read/29114257/the-rice-high-affinity-k-transporter-oshkt2-4-mediates-mg-2-homeostasis-under-high-mg-2-conditions-in-transgenic-arabidopsis
#14
Chi Zhang, Hejuan Li, Jiayuan Wang, Bin Zhang, Wei Wang, Hongxuan Lin, Sheng Luan, Jiping Gao, Wenzhi Lan
Rice (Oryza sativa; background Nipponbare) contains nine HKT (high-affinity K(+) transport)-like genes encoding membrane proteins belonging to the superfamily of Ktr/TRK/HKT. OsHKTs have been proposed to include four selectivity filter-pore-forming domains homologous to the bacterial K(+) channel KcsA, and are separated into OsHKT1s with Na(+)-selective activity and OsHKT2s with Na(+)-K(+) symport activity. As a member of the OsHKT2 subfamily, OsHKT2;4 renders Mg(2+) and Ca(2+) permeability for yeast cells and Xenopus laevis oocytes, besides K(+) and Na(+)...
2017: Frontiers in Plant Science
https://www.readbyqxmd.com/read/29108503/stress-during-development-of-experimental-endometriosis-influences-nerve-growth-and-disease-progression
#15
Marielly Cuevas, Myrella L Cruz, Antonio E Ramirez, Idhaliz Flores, Kenira J Thompson, Manuel Bayona, Michael W Vernon, Caroline B Appleyard
PURPOSE: We have previously shown that stress prior to induction worsens clinical presentation and inflammatory parameters in a rat model of endometriosis. This study was designed to examine whether stress during the development of endometriosis can affect the growth of endometriotic implants through nerve growth and immune alterations. METHODS: Endometriosis was surgically induced in female Sprague-Dawley rats by suturing uterine horn implants onto the small intestine mesentery...
January 1, 2017: Reproductive Sciences
https://www.readbyqxmd.com/read/29093296/discovery-of-peripheral-%C3%AE%C2%BA-opioid-receptor-agonists-as-novel-analgesics
#16
Shinya Suzuki, Yuji Sugawara, Hideaki Inada, Riichiro Tsuji, Atsushi Inoue, Ryuji Tanimura, Rieko Shimozono, Mitsuhiro Konno, Tomofumi Ohyama, Eriko Higashi, Chizuka Sakai, Koji Kawai
κ-Opioid receptor agonists with high selectivity over the μ-opioid receptor and peripheral selectivity are attractive targets in the development of drugs for pain. We have previously attempted to create novel analgesics with peripheral selective κ-opioid receptor agonist on the basis of TRK-820. In this study, we elucidated the biological properties of 17-hydroxy-cyclopropylmethyl and 10α-hydroxy derivatives. These compounds were found to have better κ-opioid receptor selectivity and peripheral selectivity than TRK-820...
2017: Chemical & Pharmaceutical Bulletin
https://www.readbyqxmd.com/read/29081732/lar-rptp-clustering-is-modulated-by-competitive-binding-between-synaptic-adhesion-partners-and-heparan-sulfate
#17
Seoung Youn Won, Cha Yeon Kim, Doyoun Kim, Jaewon Ko, Ji Won Um, Sung Bae Lee, Matthias Buck, Eunjoon Kim, Won Do Heo, Jie-Oh Lee, Ho Min Kim
The leukocyte common antigen-related receptor protein tyrosine phosphatases (LAR-RPTPs) are cellular receptors of heparan sulfate (HS) and chondroitin sulfate (CS) proteoglycans that direct axonal growth and neuronal regeneration. LAR-RPTPs are also synaptic adhesion molecules that form trans-synaptic adhesion complexes by binding to various postsynaptic adhesion ligands, such as Slit- and Trk-like family of proteins (Slitrks), IL-1 receptor accessory protein-like 1 (IL1RAPL1), interleukin-1 receptor accessory protein (IL-1RAcP) and neurotrophin receptor tyrosine kinase C (TrkC), to regulate synaptogenesis...
2017: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/29054983/alk-inhibitor-response-in-melanomas-expressing-eml4-alk-fusions-and-alternate-alk-isoforms
#18
Kasey L Couts, Judson Bemis, Jacqueline A Turner, Stacey M Bagby, Danielle Murphy, Jason Christiansen, Jennifer D Hintzsche, Anh Le, Todd M Pitts, Keith Wells, Allison Applegate, Carol Amato, Pratik Multani, Edna Chow-Maneval, John J Tentler, Yiqun G Shellman, Matthew J Rioth, Aik-Choon Tan, Rene Gonzalez, Theresa Medina, Robert C Doebele, William A Robinson
Oncogenic ALK fusions occur in several types of cancer and can be effectively treated with ALK inhibitors; however, ALK fusions and treatment response have not been characterized in malignant melanomas. Recently, a novel isoform of ALK (ALKATI) was reported in 11% of melanomas but the response of melanomas expressing ALKATI to ALK inhibition has not been well characterized. We analyzed 45 melanoma patient-derived xenograft models for ALK mRNA and protein expression. ALK expression was identified in 11 out of 45 (24...
October 20, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29026155/trk-fused-gene-tfg-regulates-pancreatic-%C3%AE-cell-mass-and-insulin-secretory-activity
#19
Takeshi Yamamotoya, Yusuke Nakatsu, Akifumi Kushiyama, Yasuka Matsunaga, Koji Ueda, Yuki Inoue, Masa-Ki Inoue, Hideyuki Sakoda, Midori Fujishiro, Hiraku Ono, Hiroshi Kiyonari, Hisamitsu Ishihara, Tomoichiro Asano
The Trk-fused gene (TFG) is reportedly involved in the process of COPII-mediated vesicle transport and missense mutations in TFG cause several neurodegenerative diseases including hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P). The high coincidence ratio between HMSN-P and diabetes mellitus suggests TFG to have an important role(s) in glucose homeostasis. To examine this possibility, β-cell specific TFG knockout mice (βTFG KO) were generated. Interestingly, βTFG KO displayed marked glucose intolerance with reduced insulin secretion...
October 12, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28949691/exact-fundamental-limits-of-the-first-and-second-hyperpolarizabilities
#20
Rick Lytel, Sean Mossman, Ethan Crowell, Mark G Kuzyk
Nonlinear optical interactions of light with materials originate in the microscopic response of the molecular constituents to excitation by an optical field, and are expressed by the first (β) and second (γ) hyperpolarizabilities. Upper bounds to these quantities were derived seventeen years ago using approximate, truncated state models that violated completeness and unitarity, and far exceed those achieved by potential optimization of analytical systems. This Letter determines the fundamental limits of the first and second hyperpolarizability tensors using Monte Carlo sampling of energy spectra and transition moments constrained by the diagonal Thomas-Reiche-Kuhn (TRK) sum rules and filtered by the off-diagonal TRK sum rules...
August 18, 2017: Physical Review Letters
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