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https://www.readbyqxmd.com/read/29778400/stromal-heterogeneity-in-pancreatic-cancer-and-chronic-pancreatitis
#1
Lena Haeberle, Katja Steiger, Anna Melissa Schlitter, Sami Alexander Safi, Wolfram Trudo Knoefel, Mert Erkan, Irene Esposito
BACKGROUND/OBJECTIVES: An abundant stromal reaction is a hallmark of pancreatic ductal adenocarcinoma (PDAC) and chronic pancreatitis (CP). The cells mainly responsible for the stromal reaction are activated pancreatic stellate cells (PSCs). Despite their crucial role, PSCs are not well characterized. PSCs share characteristics with the better-known hepatic stellate cells (HSCs). The aim of this study was a detailed analysis of PSCs in PDAC and CP. METHODS: Whole-slide specimens of CP (n = 12) and PDAC (n = 10) were studied by histochemistry and immunohistochemistry...
May 12, 2018: Pancreatology: Official Journal of the International Association of Pancreatology (IAP) ... [et Al.]
https://www.readbyqxmd.com/read/29753009/the-implications-of-trka-and-met-aberrations-in-de-novo-salivary-duct-carcinoma
#2
Hyang Joo Ryu, Yoon Woo Koh, Sun Och Yoon
Salivary duct carcinoma (SDC) is an aggressive carcinoma with poor prognosis. Although anti-HER2 therapy is a potential treatment option for HER2-positive SDC, other potential therapeutic targets are not known, in particular for HER2-negative cases. In this study, the recently identified receptor tyrosine kinases MET and tropomyosin-receptor kinase (Trk) were investigated as potential therapeutic targets. A total of 28 consecutive, surgically resected, de novo SDC cases were selected after evaluating histology and immunohistochemical expression of androgen receptor...
May 9, 2018: Human Pathology
https://www.readbyqxmd.com/read/29752567/inhibiting-ezh2-rescued-bupivacaine-induced-neuronal-apoptosis-in-spinal-cord-dorsal-root-ganglia-in-mice
#3
Jinwei Zheng, Junping Chen, Guorong Wu, Chaoshuang Wu, Ruichun Wang, Wei Wang
PURPOSE: In the present work, we intended to explore the function of enhancer of zeste homolog 2 (EZH2) in modulated anesthetic reagent bupivacaine-induced neuronal apoptosis in spinal cord dorsal root ganglia (DRG). METHODS: Murine DRG explant was treated with 5 mM bupivacaine in vitro to induce neuronal apoptosis, which was examined by a TUNEL assay. Protein and mRNA expressions of EZH2 in bupivacaine-treated DRG were examined by western blot and qRT-PCR assays...
May 11, 2018: Journal of Anesthesia
https://www.readbyqxmd.com/read/29750782/hey1-and-p53-dependent-trkc-proapoptotic-activity-controls-neuroblastoma-growth
#4
Marie Ménard, Clélia Costechareyre, Gabriel Ichim, Jonathan Blachier, David Neves, Loraine Jarrosson-Wuilleme, Reinhard Depping, Jan Koster, Pierre Saintigny, Patrick Mehlen, Servane Tauszig-Delamasure
The neurotrophin-3 (NT-3) receptor tropomyosin receptor kinase C (TrkC/NTRK3) has been described as a dependence receptor and, as such, triggers apoptosis in the absence of its ligand NT-3. This proapoptotic activity has been proposed to confer a tumor suppressor activity to this classic tyrosine kinase receptor (RTK). By investigating interacting partners that might facilitate TrkC-induced cell death, we have identified the basic helix-loop-helix (bHLH) transcription factor Hey1 and importin-α3 (karyopherin alpha 4 [KPNA4]) as direct interactors of TrkC intracellular domain, and we show that Hey1 is required for TrkC-induced apoptosis...
May 11, 2018: PLoS Biology
https://www.readbyqxmd.com/read/29672039/discovery-of-allosteric-potent-subtype-selective-and-peripherally-restricted-trka-kinase-inhibitors
#5
Sharan K Bagal, Kiyoyuki Omoto, David C Blakemore, Peter J Bungay, James G Bilsland, Philip J Clarke, Matthew S Corbett, Ciarán N Cronin, Jingrong Jean Cui, Rebecca Dias, Neil J Flanagan, Samantha E Greasley, Rachel Grimley, Eric Johnson, David Fengas, Linda Kitching, Michelle L Kraus, Indrawan McAlpine, Asako Nagata, Gareth J Waldron, Joseph S Warmus
Tropomyosin receptor kinases are a family of three tyrosine kinases (TrkA, TrkB, TrkC) activated by peptide hormones of the neurotrophin family: nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin 3 (NT3) and neurotrophin 4 (NT4). The NGF antibody tanezumab has provided clinical proof of concept for inhibition of the TrkA kinase pathway in pain. In turn, this has led to significant interest in the development of small molecule inhibitors of TrkA as an alternative intervention point on the NGF pathway...
April 19, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29617282/inhibiting-trk-proteins-in-clinical-cancer-therapy
#6
REVIEW
Allison M Lange, Hui-Wen Lo
Gene rearrangements resulting in the aberrant activity of tyrosine kinases have been identified as drivers of oncogenesis in a variety of cancers. The tropomyosin receptor kinase (TRK) family of tyrosine receptor kinases is emerging as an important target for cancer therapeutics. The TRK family contains three members, TRKA, TRKB, and TRKC, and these proteins are encoded by the genes NTRK1, NTRK2, and NTRK3, respectively. To activate TRK receptors, neurotrophins bind to the extracellular region stimulating dimerization, phosphorylation, and activation of downstream signaling pathways...
April 4, 2018: Cancers
https://www.readbyqxmd.com/read/29581981/mechanism-of-activating-the-proprioceptive-nt-3-trkc-signalling-pathway-by-reverse-intervention-for-the-anterior-cruciate-ligament-hamstring-reflex-arc-with-electroacupuncture
#7
Lei Zhang, Yan Zeng, Ji Qi, Taiyuan Guan, Xin Zhou, Yancheng He, Guoyou Wang, Shijie Fu
The anterior cruciate ligament (ACL) is an important structure maintaining stability of the knee joints. Deficits in physical stability and the proprioceptive capabilities of the knee joints are observed, when the ACL is damaged. Additionally, a unilateral ACL injury can affect bilateral knee proprioception; therefore, proprioception of the ACL may play a key role in stability. Electroacupuncture therapy has a definite effect nerve regeneration. In this study, cynomolgus monkeys were randomly divided into 4 groups: the model control group, intervention of the injured knee with electroacupuncture (IIKE) group, intervention of the bilateral knees with electroacupuncture (IBKE) group, and the blank control group...
2018: BioMed Research International
https://www.readbyqxmd.com/read/29569362/temporally-restricted-death-and-the-role-of-p75ntr-as-a-survival-receptor-in-the-developing-sensory-nervous-system
#8
Irene Cheng, Lucy Jin, Lucy C Rose, Christopher D Deppmann
The peripheral somatosensory system overproduces neurons early in development followed by a period of cell death during final target innervation. The decision to survive or die in somatosensory neurons of the dorsal root ganglion (DRG) is mediated by target derived neurotrophic factors and their cognate receptors. Subsets of peripheral somatosensory neurons can be crudely defined by the neurotrophic receptors that they express: peptidergic nociceptors (TrkA+), non-peptidergic nociceptors (Ret+), mechanoreceptors (Ret+ or TrkB+), and proprioceptors (TrkC+)...
March 22, 2018: Developmental Neurobiology
https://www.readbyqxmd.com/read/29540150/expression-of-brain-derived-neurotrophic-factor-in-kidneys-from-normal-and-cyclosporine-treated-rats
#9
Yuan Sheng Tao, Shang Guo Piao, Ying Shun Jin, Ji Zhe Jin, Hai Lan Zheng, Hai Yan Zhao, Sun Woo Lim, Chul Woo Yang, Can Li
BACKGROUND: Accumulating evidence suggests that a decrease in brain-derived neurotrophic factor (BDNF) level induces a variety of psychiatric and neurological disorders. However, the expression and role of BDNF in the kidney have not been explored. The present study examined the expression of BDNF and tropomyosin-related kinase (Trk) receptors in an experimental model of chronic cyclosporine A (CsA) nephropathy. METHODS: Sprague-Dawley rats on a salt-deplete diet were treated daily for four weeks with vehicle or CsA...
March 14, 2018: BMC Nephrology
https://www.readbyqxmd.com/read/29523879/aav1-nt-3-gene-therapy-increases-muscle-fiber-diameter-through-activation-of-mtor-pathway-and-metabolic-remodeling-in-a-cmt-mouse-model
#10
Mehmet E Yalvac, Jakkrit Amornvit, Lei Chen, Kimberly M Shontz, Sarah Lewis, Zarife Sahenk
Neurotrophin 3 (NT-3) has well-recognized effects on peripheral nerve and Schwann cells, promoting axonal regeneration and associated myelination. In this study, we assessed the effects of AAV.NT-3 gene therapy on the oxidative state of the neurogenic muscle from the TremblerJ (Tr J ) mice at 16 weeks post-gene injection and found that the muscle fiber size increase was associated with a change in the oxidative state of muscle fibers towards normalization of the fiber type ratio seen in the wild type. NT-3-induced fiber size increase was most prominent for the fast twitch glycolytic fiber population...
April 2018: Gene Therapy
https://www.readbyqxmd.com/read/29456805/click-addressable-cassette-for-photoaffinity-labeling
#11
Bosheng Zhao, Kevin Burgess
A small molecule 1 was designed to contain an alkyne, a trifluoromethyl phenyldiazirine, and a free piperidine- NH for facile conjugation to protein binding ligands. This "cassette" 1 was synthesized via a relatively direct route involving only routine steps. In this proof-of-concept study, putative ligands for carbonic anhydrase IX and for TrkC were conjugated to 1 . Photoaffinity labeling was performed using purified extracellular regions of both these protein-receptors, and using cells that express these receptors (isolation via a pull-down procedure), labeling of the protein was observed in all four experiments...
February 8, 2018: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29453932/neurotrophin-3-restores-synaptic-plasticity-in-the-striatum-of-a-mouse-model-of-huntington-s-disease
#12
Victor G Gómez-Pineda, Francisco M Torres-Cruz, César I Vivar-Cortés, Elizabeth Hernández-Echeagaray
AIMS: Neurotrophin-3 (NT-3) is expressed in the mouse striatum; however, it is not clear the NT-3 role in striatal physiology. The expression levels of mRNAs and immune localization of the NT-3 protein and its receptor TrkC are altered in the striatum following damage induced by an in vivo treatment with 3-nitropropionic acid (3-NP), a mitochondrial toxin used to mimic the histopathological hallmarks of Huntington's disease (HD). The aim of this study was to evaluate the role of NT-3 on corticostriatal synaptic transmission and its plasticity in both the control and damaged striatum...
April 2018: CNS Neuroscience & Therapeutics
https://www.readbyqxmd.com/read/29380702/biological-and-genetic-features-of-neuroblastoma-and-their-clinical-importance
#13
Nevim Aygun
Neuroblastoma derived from primitive cells of the sympathetic nervous system typically develops in the adrenal medulla or paraspinal ganglia. Neuroblastoma usually occurs sporadically, but familial cases are also observed. ALK and PHOX2B germline mutations can cause hereditary neuroblastoma, while a common genetic variation in chromosome 6p22 is associated to sporadic neuroblastoma. However, the aetiology of sporadic neuroblastoma is not exactly known. This embryonic malignancy generally represents the second most common solid tumour after central nervous system tumours throughout the world in childhood...
January 28, 2018: Current Pediatric Reviews
https://www.readbyqxmd.com/read/29312563/trkb-promotes-laryngeal-cancer-metastasis-via-activation-pi3k-akt-pathway
#14
Liang Jiang, Zhihai Wang, Chuan Liu, Zhitao Gong, Yucheng Yang, Houyong Kang, Yanshi Li, Guohua Hu
Objectives: The aim of our study was to investigate the role of TrkB pathway in tumor occurrence and development for in order to provide theoretical basis to laryngeal cancer therapy. Materials and methods: Biological characteristics of the cells were studied by migration tests and colony forming assay. Gene and protein expression analysis was performed by RT-PCR or western blot. in vivo experiments were conducted in syngeneic BALB/c mice. Results: Significant changes in protein and gene expression, including higher expression level of TrkB, were found in cells and laryngeal cancer specimens...
December 12, 2017: Oncotarget
https://www.readbyqxmd.com/read/29260495/caffeic-acid-phenethyl-ester-cape-protects-pc12-cells-from-cisplatin-induced-neurotoxicity-by-activating-the-ngf-signaling-pathway
#15
Rafaela Scalco Ferreira, Neife Aparecida Guinaim Dos Santos, Nádia Maria Martins, Laís Silva Fernandes, Antonio Cardozo Dos Santos
Cisplatin is a highly effective chemotherapeutic drug that is toxic to the peripheral nervous system. Findings suggest that axons are early targets of the neurotoxicity of cisplatin. Although many compounds have been reported as neuroprotective, there is no effective treatment against the neurotoxicity of cisplatin. Caffeic acid phenethyl ester (CAPE) is a propolis component with neuroprotective potential mainly attributed to antioxidant and anti-inflammatory mechanisms. We have recently demonstrated the neurotrophic potential of CAPE in a cellular model of neurotoxicity related to Parkinson's disease...
December 19, 2017: Neurotoxicity Research
https://www.readbyqxmd.com/read/29242588/in-retinitis-pigmentosa-trkc-t1-dependent-vectorial-erk-activity-upregulates-glial-tnf-%C3%AE-causing-selective-neuronal-death
#16
Alba Galán, Sean Jmaeff, Pablo F Barcelona, Fouad Brahimi, Marinko V Sarunic, H Uri Saragovi
In some diseases the TrkC.T1 isoform is upregulated in glia, associated with glial TNF-α production and neuronal death. What remains unknown are the activating signals in glia, and how paracrine signals may be selective for a targeted neuron while sparing other proximate neurons. We studied these questions in the retina, where Müller glia contacts photoreceptors on one side and retinal ganglion cells on the other. In a mutant Rhodopsin mouse model of retinitis pigmentosa (RP) causing progressive photoreceptor death-but sparing retinal ganglion cells-TrkC...
December 14, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/29237803/antitumor-activity-of-entrectinib-a-pan-trk-ros1-and-alk-inhibitor-in-etv6-ntrk3-positive-acute-myeloid-leukemia
#17
Kristen M Smith, Patrick C Fagan, Elena Pomari, Giuseppe Germano, Chiara Frasson, Colin Walsh, Ian 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...
February 2018: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29222769/neurotrophic-factors-an-overview
#18
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/29162704/tropomyosin-related-kinase-c-trkc-enhances-podocyte-migration-by-erk-mediated-wave2-activation
#19
Sascha Gromnitza, Carolin Lepa, Thomas Weide, Albrecht Schwab, Hermann Pavenstädt, Britta George
Podocyte malfunction is central to glomerular diseases and is marked by defective podocyte intercellular junctions and actin cytoskeletal dynamics. Podocytes share many morphologic features with neurons, so that similar sets of proteins appear to regulate cell process formation. One such protein is the tropomyosin-related kinase C (TrkC). TrkC deficiency in mice leads to proteinuria as a surrogate of defective kidney filter function. Activation of endogenous TrkC by its ligand neurotrophin-3 resulted in increased podocyte migration-a surrogate of podocyte actin dynamics in vivo...
March 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/29118225/activity-of-entrectinib-in-a-patient-with-the-first-reported-ntrk-fusion-in-neuroendocrine-cancer
#20
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 NTRK 1, 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
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