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https://www.readbyqxmd.com/read/29118225/activity-of-entrectinib-in-a-patient-with-the-first-reported-ntrk-fusion-in-neuroendocrine-cancer
#1
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
#2
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
#3
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
#4
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
#5
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
#6
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
#7
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
#8
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
https://www.readbyqxmd.com/read/28924861/role-of-bdnf-and-neurotrophic-receptors-in-human-inner-ear-development
#9
L Johnson Chacko, M J F Blumer, E Pechriggl, H Rask-Andersen, W Dietl, A Haim, H Fritsch, R Glueckert, J Dudas, A Schrott-Fischer
The expression patterns of the neurotrophin, brain-derived neurotrophic factor, BDNF, and the neurotrophic receptors-p75NTR and Trk receptors-in the developing human fetal inner ear between the gestational weeks (GW) 9 to 12 are examined via in situ hybridization and immunohistochemistry. BDNF mRNA expression was highest in the cochlea at GW 9 but declined in the course of development. In contrast to embryonic murine specimens, a decline in BDNF expression from the apical to the basal turn of the cochlea could not be observed...
September 19, 2017: Cell and Tissue Research
https://www.readbyqxmd.com/read/28903424/identification-and-characterization-of-a-novel-scyl3-ntrk1-rearrangement-in-a-colorectal-cancer-patient
#10
Massimo Milione, Elena Ardini, Jason Christiansen, Emanuele Valtorta, Silvio Veronese, Roberta Bosotti, Alessio Pellegrinelli, Adele Testi, Filippo Pietrantonio, Giovanni Fucà, Ge Wei, Danielle Murphy, Salvatore Siena, Antonella Isacchi, Filippo De Braud
In colorectal cancer patients, chromosomal rearrangements involving NTRK1 gene (encoding the TRKA protein) are shown in a small subset of patients and are associated with the constitutive activation of the kinase domain of TRKA. In turn, activated TRKA-fusion proteins are associated with proliferation and survival in colorectal cancer tumors. Here we report the identification and functional characterization of a new SCYL3-NTRK1 fusion gene in a 61-year-old colorectal cancer patient. To our knowledge, this fusion protein has never been previously documented in oncological patients...
August 15, 2017: Oncotarget
https://www.readbyqxmd.com/read/28884193/neurotrophin-trk-receptors-new-targets-for-cancer-therapy
#11
Jacopo Meldolesi
In the last few years, exciting reports have emerged regarding the role of the two types of neurotrophin receptors, p75(NTR) and Trks, not only in neurons, where they were discovered, but also in non-neural cells and, especially, in numerous cancers, including breast, lung, colon-rectum, pancreas, prostate, glioblastoma, neuroblastoma, myeloma, and lymphoid tumors. Traditionally, p75(NTR), activated by all neurotrophins and their precursors, is an inhibitor. In various cancers, however, activated p75(NTR) induces variable effects, from inhibition to stimulation of cell proliferation, dependent on their direct or coordinate/indirect mechanism(s) of action...
September 8, 2017: Reviews of Physiology, Biochemistry and Pharmacology
https://www.readbyqxmd.com/read/28870922/hedgehog-inhibition-upregulates-trk-expression-to-antagonize-tumor-suppression-in-small-cell-lung-cancer-cells
#12
Hideya Onishi, Katsuya Nakamura, Shuntaro Nagai, Kosuke Yanai, Akio Yamasaki, Makoto Kawamoto, Akira Imaizumi, Takashi Morisaki
BACKGROUND/AIM: Previously we have shown that tropomyosin-related kinase B (TRKB) and Hedgehog (Hh) signalling pathways induce malignant phenotypes in many cancer types. However, results from small cell lung cancer (SCLC) clinical trials using TRK and Hh inhibitors have been disappointing. One reason for this may be the existence of crosstalk between TRKB and Hh signalling pathways. In this study, we detected negative crosstalk between the TRKB and Hh-GLI1 signalling pathways. MATERIALS AND METHODS: The human small cell lung carcinoma cell line, SBC-5, was used...
September 2017: Anticancer Research
https://www.readbyqxmd.com/read/28864638/fast-trking-drug-development-for-rare-molecular-targets
#13
Aparna R Parikh, Ryan B Corcoran
Drug development for rare molecular targets in oncology presents unique challenges. In this issue of Cancer Discovery, Drilon and colleagues report the accelerated development and innovative initial clinical trial strategy of a next-generation TRK inhibitor, LOXO-195, designed to overcome common secondary TRK resistance mutations. Cancer Discov; 7(9); 934-6. ©2017 AACR.See related article by Drilon et al., p. 963.
September 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28851831/tfg-facilitates-outer-coat-disassembly-on-copii-transport-carriers-to-promote-tethering-and-fusion-with-er-golgi-intermediate-compartments
#14
Michael G Hanna, Samuel Block, E B Frankel, Feng Hou, Adam Johnson, Lin Yuan, Gavin Knight, James J Moresco, John R Yates, Randolph Ashton, Randy Schekman, Yufeng Tong, Anjon Audhya
The conserved coat protein complex II (COPII) mediates the initial steps of secretory protein trafficking by assembling onto subdomains of the endoplasmic reticulum (ER) in two layers to generate cargo-laden transport carriers that ultimately fuse with an adjacent ER-Golgi intermediate compartment (ERGIC). Here, we demonstrate that Trk-fused gene (TFG) binds directly to the inner layer of the COPII coat. Specifically, the TFG C terminus interacts with Sec23 through a shared interface with the outer COPII coat and the cargo receptor Tango1/cTAGE5...
September 12, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28846707/kek-6-a-truncated-trk-like-receptor-for-drosophila-neurotrophin-2-regulates-structural-synaptic-plasticity
#15
Suzana Ulian-Benitez, Simon Bishop, Istvan Foldi, Jill Wentzell, Chinenye Okenwa, Manuel G Forero, Bangfu Zhu, Marta Moreira, Mark Phizacklea, Graham McIlroy, Guiyi Li, Nicholas J Gay, Alicia Hidalgo
Neurotrophism, structural plasticity, learning and long-term memory in mammals critically depend on neurotrophins binding Trk receptors to activate tyrosine kinase (TyrK) signaling, but Drosophila lacks full-length Trks, raising the question of how these processes occur in the fly. Paradoxically, truncated Trk isoforms lacking the TyrK predominate in the adult human brain, but whether they have neuronal functions independently of full-length Trks is unknown. Drosophila has TyrK-less Trk-family receptors, encoded by the kekkon (kek) genes, suggesting that evolutionarily conserved functions for this receptor class may exist...
August 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28817795/hippocampal-dentate-mossy-cells-improve-their-cv-and-trk-into-the-limelight
#16
Aaron D Milstein, Ivan Soltesz
The impact of dentate mossy cells on hippocampal activity remained uncertain despite a long history of investigation. In this issue of Neuron, Hashimotodani et al. (2017) discover a presynaptically expressed form of long-term potentiation at mossy cell outputs, shedding light on their mysterious function.
August 16, 2017: Neuron
https://www.readbyqxmd.com/read/28770018/brain-derived-neurotrophic-factor-attenuates-septic-myocardial-dysfunction-via-enos-no-pathway-in-rats
#17
Ni Zeng, Junmei Xu, Weifeng Yao, Suobei Li, Wei Ruan, Feng Xiao
Sepsis-induced myocardial dysfunction increases mortality in sepsis, yet the underlying mechanism is unclear. Brain-derived neurotrophic factor (BDNF) has been found to enhance cardiomyocyte function, but whether BDNF has a beneficial effect against septic myocardial dysfunction is unknown. Septic shock was induced by cecal ligation and puncture (CLP). BDNF was expressed in primary cardiomyocytes, and its expression was significantly reduced after sepsis. In rats with sepsis, a sharp decline in survival was observed after CLP, with significantly reduced cardiac BDNF expression, enhanced myocardial fibrosis, elevated oxidative stress, increased myocardial apoptosis, and decreased endothelial nitric oxide (NO) synthase (eNOS) and NO...
2017: Oxidative Medicine and Cellular Longevity
https://www.readbyqxmd.com/read/28767387/identification-and-characterization-of-a-novel-scyl3-ntrk1-rearrangement-in-a-colorectal-cancer-patient
#18
Massimo Milione, Elena Ardini, Jason Christiansen, Emanuele Valtorta, Silvio Veronese, Roberta Bosotti, Alessio Pellegrinelli, Adele Testi, Filippo Pietrantonio, Giovanni Fucà, Ge Wei, Danielle Murphy, Salvatore Siena, Antonella Isacchi, Filippo De Braud
In colorectal cancer patients, chromosomal rearrangements involving NTRK1 gene (encoding the TRKA protein) are shown in a small subset of patients and are associated with the constitutive activation of the kinase domain of TRKA. In turn, activated TRKA-fusion proteins are associated with proliferation and survival in colorectal cancer tumors.Here we report the identification and functional characterization of a new SCYL3-NTRK1 fusion gene in a 61-year-old colorectal cancer patient. To our knowledge, this fusion protein has never been previously documented in oncological patients...
July 24, 2017: Oncotarget
https://www.readbyqxmd.com/read/28744222/presence-of-functional-neurotrophin-trkb-receptors-in-the-rat-superior-cervical-ganglion
#19
Pablo Valle-Leija, Angeles Cancino-Rodezno, Berardo M Sánchez-Tafolla, Erwin Arias, Diana Elinos, Jessica Feria, María E Zetina, Miguel A Morales, Fredy Cifuentes
Sympathetic neurons express the neurotrophin receptors TrkA, p75NTR, and a non-functional truncated TrkB isoform (TrkB-Tc), but are not thought to express a functional full-length TrkB receptor (TrkB-Fl). We, and others, have demonstrated that nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF) modulate synaptic transmission and synaptic plasticity in neurons of the superior cervical ganglion (SCG) of the rat. To clarify whether TrkB is expressed in sympathetic ganglia and contributes to the effects of BDNF upon sympathetic function, we characterized the presence and activity of the neurotrophin receptors expressed in the adult SCG compared with their presence in neonatal and cultured sympathetic neurons...
2017: Frontiers in Physiology
https://www.readbyqxmd.com/read/28719467/pan-trk-immunohistochemistry-is-an-efficient-and-reliable-screen-for-the-detection-of-ntrk-fusions
#20
Jaclyn F Hechtman, Ryma Benayed, David M Hyman, Alexander Drilon, Ahmet Zehir, Denise Frosina, Maria E Arcila, Snjezana Dogan, David S Klimstra, Marc Ladanyi, Achim A Jungbluth
Activating neurotrophic tyrosine receptor kinase (NTRK) fusions, typically detected using nucleic-acid based assays, are highly targetable and define certain tumors. Here, we explore the utility of pan-TRK immunohistochemistry (IHC) to detect NTRK fusions. NTRK rearrangements were detected prospectively using MSK-IMPACT, a DNA-based next-generation sequencing assay. Transcription of novel NTRK rearrangements into potentially functional fusion transcripts was assessed via Archer Dx fusion assay. Pan-Trk IHC testing with mAb EPR17341 was performed on all NTRK rearranged cases and 20 cases negative for NTRK fusions on Archer...
November 2017: American Journal of Surgical Pathology
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