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https://www.readbyqxmd.com/read/28319380/evaluation-and-characterization-of-trk-kinase-inhibitors-for-the-treatment-of-pain-reliable-binding-affinity-predictions-from-theory-and-computation
#1
Shunzhou Wan, Agastya P Bhati, Sarah Skerratt, Kiyoyuki Omoto, Veerabahu Shanmugasundaram, Sharan K Bagal, Peter Vivian Coveney
Optimisation of ligand binding affinity to the target protein of interest is a primary objective in small-molecule drug discovery. Until now, the prediction of binding affinities by computational methods has not been widely applied in the drug discovery process, mainly due to its lack of accuracy and reproducibility, as well as the long turnaround times required to obtain results. Herein, we report on a collaborative study that compares tropomyosin receptor kinase A (TrkA) binding affinity predictions using two recently formulated fast computational approaches - namely ESMACS (Enhanced Sampling of Molecular dynamics with Approximation of Continuum Solvent) and TIES (Thermodynamic Integration with Enhanced Sampling) - to experimentally derived TrkA binding affinities for a set of Pfizer pan-Trk compounds...
March 20, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28315978/the-hallucinogen-2-5-dimethoxy-4-iodoamphetamine-hydrochloride-activates-neurotrophin-receptors-in-a-neuronal-cell-line-and-promotes-neurites-extension
#2
Zoya Marinova, Susanne Walitza, Edna Grünblatt
Decreased neurotrophic factors expression and neurotrophin receptors signalling have repeatedly been reported in association with stress, depression, and neurodegenerative disorders. We have previously identified the hallucinogen 2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI) as protective against trophic deprivation-induced cytotoxicity in human neuroblastoma SK-N-SH cells and established the dependence of this effect on the 5-HT2A receptor, tyrosine kinases activity, and the extracellular signal-regulated kinase pathway...
March 18, 2017: Journal of Neural Transmission
https://www.readbyqxmd.com/read/28290778/improved-neural-microcirculation-and-regeneration-after-peripheral-nerve-decompression-in-dpn-rats
#3
Wenxiang Zhong, Min Yang, Wenchuan Zhang, Massimiliano Visocchi, Xiangjun Chen, Chenlong Liao
OBJECTIVE: Recently, neural microcirculation and regeneration were regarded as critical factors in diabetic peripheral neuropathy (DPN) improvement. In the present study, we explored the cytological and molecular mechanisms how peripheral nerve decompression impaired nerve injury. METHODS: Forty-five male SD rats were established as the DPN model. HE staining was used to observe the morphology and distribution of microvessels. Transmission electron microscopy was applied to observe the morphology and distribution of Schwann cells...
March 14, 2017: Neurological Research
https://www.readbyqxmd.com/read/28282920/prongf-but-not-ngf-switches-from-neurotrophic-to-apoptotic-activity-in-response-to-reductions-in-trka-receptor-levels
#4
Maria S Ioannou, Margaret Fahnestock
Nerve growth factor (NGF) promotes the survival and differentiation of neurons. NGF is initially synthesized as a precursor, proNGF, which is the predominant form in the central nervous system. NGF and proNGF bind to TrkA/p75NTR to mediate cell survival and to sortilin/p75NTR to promote apoptosis. The ratio of TrkA to p75NTR affects whether proNGF and mature NGF signal cell survival or apoptosis. The purpose of this study was to determine whether the loss of TrkA influences p75NTR or sortilin expression levels, and to establish whether proNGF and mature NGF have a similar ability to switch between cell survival and cell death...
March 9, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28280935/crypt-cell-markers-in-the-olfactory-organ-of-poecilia-reticulata-analysis-and-comparison-with-the-fish-model-danio-rerio
#5
Simone Bettini, Liliana Milani, Maurizio Lazzari, Maria Gabriella Maurizii, Valeria Franceschini
Olfactory crypt neurons have been observed in several bony fishes and chondrichtyans. Although their morphology is uniform in all fish, very few is known about their antigenic properties, usually studied in zebrafish, but quite overlooked in other species. We tested in Poecilia reticulata (guppy) the two antibodies recognized to mark zebrafish crypt cells: while anti-S100 showed an immunohistochemical pattern comparable to what reported in zebrafish, anti-TrkA gave no signal. Western blot analysis revealed that S100-antiserum bound an antigen of expected weight, probably belonging to the S100 family...
March 9, 2017: Brain Structure & Function
https://www.readbyqxmd.com/read/28279735/development-of-a-pharmacodynamic-biomarker-to-measure-target-engagement-from-inhibition-of-the-ngf-trka-pathway
#6
Eric A Price, Alicja Krasowska-Zoladek, Kausik K Nanda, Shawn J Stachel, Darrell A Henze
BACKGROUND: NGF signaling through TrkA triggers pathways involved in a wide range of biological effects. Clinical trials targeting either NGF or TrkA are ongoing to treat various diseases in the areas of oncology, neuroscience, and for pain, but there is no described measure of target engagement of TrkA in these studies. NEW METHOD: We have developed custom ELISA assays to measure NGF-induced phosphorylation of TrkA specific for rodent and human receptors. Optimized tissue processing methods allow for detection in both the brain and in skin...
March 7, 2017: Journal of Neuroscience Methods
https://www.readbyqxmd.com/read/28270361/morphological-and-immunohistochemical-comparison-of-intrapancreatic-nerves-between-chronic-pancreatitis-and-type-1-autoimmune-pancreatitis
#7
Kota Kato, Tsukasa Ikeura, Masato Yanagawa, Takashi Tomiyama, Toshiro Fukui, Kazushige Uchida, Makoto Takaoka, Akiyoshi Nishio, Yoshiko Uemura, Sohei Satoi, Hisao Yamada, Kazuichi Okazaki
OBJECTIVES: The abdominal pain associated with chronic pancreatitis (CP) may be related to the increased number and size of intrapancreatic nerves. On the other hand, patients with type 1 autoimmune pancreatitis (AIP) rarely suffer from the pain syndrome, and there are no previous studies concerning the histopathological findings of intrapancreatic nerves in patients with type 1 AIP. The current study is aimed at investigating the differences in the histopathological and immunohistochemical findings of intrapancreatic nerves in patients with CP and type 1 AIP...
February 20, 2017: Pancreatology: Official Journal of the International Association of Pancreatology (IAP) ... [et Al.]
https://www.readbyqxmd.com/read/28270021/tropomyosin-receptor-kinase-inhibitors-an-updated-patent-review-for-2010-2016-part-ii
#8
Justin J Bailey, Ralf Schirrmacher, Kristen Farrell, Vadim Bernard-Gauthier
TrkA/B/C receptor activation supports growth, survival, and differentiation of discrete neuronal populations during development, adult life, and ageing but also plays numerous roles in human disease onset and progression. Trk-specific inhibitors have therapeutic applications in cancer and pain and thus constitute a growing area of interest in oncology and neurology. There has been substantial growth in the number of structural classes of Trk inhibitors and the number of industrial entrants to the Trk inhibitor field over the past six years...
March 8, 2017: Expert Opinion on Therapeutic Patents
https://www.readbyqxmd.com/read/28270010/tropomyosin-receptor-kinase-inhibitors-an-updated-patent-review-for-2010-2016-part-i
#9
Justin J Bailey, Ralf Schirrmacher, Kristen Farrell, Vadim Bernard-Gauthier
Tropomyosin receptor kinases (TrkA/B/C) play crucial roles in the development and maintenance of the nervous system, and aberrant expression of Trk has been implicated in neurological disorders as well as neural and non-neural neoplasms. Patent activity encompassing Trk inhibitors has grown substantially over the last 6 years, recognized by a rise in the number of pharmaceutical entrants to the field and the escalation of novel inhibitor chemotypes. Area covered: In Part I of this two part review, a biological and structural overview of Trk is provided in the context of Trk as a therapeutic target for cancer and pain, followed by the report of recent patent literature claiming small molecule inhibitors of Trk family kinases or which describe inhibitors developed for other kinase targets but include noteworthy Trk inhibition/application...
March 8, 2017: Expert Opinion on Therapeutic Patents
https://www.readbyqxmd.com/read/28266869/pig-induced-pluripotent-stem-cell-derived-neural-rosettes-parallel-human-differentiation-into-sensory-neural-subtypes
#10
Robin L Webb, Amalia Gallegos-Cárdenas, Colette N Miller, Nicholas J Solomotis, Hong-Xiang Liu, Franklin D West, Steven L Stice
The pig is the large animal model of choice for study of nerve regeneration and wound repair. Availability of porcine sensory neural cells would conceptually allow for analogous cell-based peripheral nerve regeneration in porcine injuries of similar severity and size to those found in humans. After recently reporting that porcine (or pig) induced pluripotent stem cells (piPSCs) differentiate into neural rosette (NR) structures similar to human NRs, here we demonstrate that pig NR cells could differentiate into neural crest cells and other peripheral nervous system-relevant cell types...
March 7, 2017: Cellular Reprogramming
https://www.readbyqxmd.com/read/28255018/acute-lymphoblastic-leukemia-with-aleukemic-prodrome-preleukemic-dynamics-and-possible-mechanisms-of-immunosurveillance
#11
Olga Zimmermannova, Marketa Zaliova, Anthony V Moorman, Halima Al-Shehhi, Eva Fronkova, Zuzana Zemanova, Tomas Kalina, Ajay Vora, Jan Stary, Jan Trka, Ondrej Hrusak, Jan Zuna
No abstract text is available yet for this article.
March 2, 2017: Haematologica
https://www.readbyqxmd.com/read/28254884/a-functional-coupling-between-crmp1-and-nav1-7-for-retrograde-propagation-of-semaphorin3a-signaling
#12
Masayuki Yamane, Naoya Yamashita, Tomonobu Hida, Yoshinori Kamiya, Fumio Nakamura, Pappachan Kolattukudy, Yoshio Goshima
Semaphorin3A (Sema3A) is a secreted type of axon guidance molecules that regulates axon wiring through neuropilin-1 (NRP1) and PlexinAs (PlexAs) receptor complex. Sema3A regulates the dendritic branching through a tetrodotoxin (TTX)-sensitive retrograde axonal transport of PlexAs and Tropomyosin-related kinase A (TrkA) complex. We here demonstrate that Nav1.7, a TTX-sensitive Na(+) channel, by coupling with collapsin response mediator protein 1 (CRMP1), mediates the Sema3A-induced retrograde transport. In mouse dorsal root ganglion (DRG) neurons, Sema3A increased co-localization of PlexA4 and TrkA in the growth cones and axons...
March 2, 2017: Journal of Cell Science
https://www.readbyqxmd.com/read/28253191/%C3%AE-ngf-and-%C3%AE-ngf-receptor-upregulation-in-blood-and-synovial-fluid-in-osteoarthritis
#13
Claudia Montagnoli, Roberto Tiribuzi, Lucia Crispoltoni, Alessandra Pistilli, Anna Maria Stabile, Francesco Manfreda, Giacomo Placella, Mario Rende, Giuliano Cerulli
Osteoarthritis (OA) of the knee is the most common form of non traumatic joint disease. Previous studies have shown the involvement of β-NGF and its receptors TrKA and p75NTR in OA-related pain, but their role in its pathogenesis is still unclear. The aim of our study was to investigate the amount of β-NGF and the expression levels of its receptors on cells isolated from synovial fluid and blood from OA patients who had undergone total knee arthroplasty, in order to check any possible correlation with the disease staging...
March 2, 2017: Biological Chemistry
https://www.readbyqxmd.com/read/28245631/role-of-nerve-growth-factor-ngf-and-mirnas-in-epithelial-ovarian-cancer
#14
REVIEW
Rocío Retamales-Ortega, Lorena Oróstica, Carolina Vera, Paula Cuevas, Andrea Hernández, Iván Hurtado, Margarita Vega, Carmen Romero
Ovarian cancer is the eighth most common cancer in women worldwide, and epithelial ovarian cancer (EOC) represents 90% of cases. Nerve growth factor (NGF) and its high affinity receptor tyrosine kinase A receptor (TRKA) have been associated with the development of several types of cancer, including EOC; both NGF and TRKA levels are elevated in this pathology. EOC presents high angiogenesis and several molecules have been reported to induce this process. NGF increases angiogenesis through its TRKA receptor on endothelial cells, and by indirectly inducing vascular endothelial growth factor expression...
February 26, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28244980/next-generation-sequencing-indicates-false-positive-mrd-results-and-better-predicts-prognosis-after-sct-in-patients-with-childhood-all
#15
M Kotrova, V H J van der Velden, J J M van Dongen, R Formankova, P Sedlacek, M Brüggemann, J Zuna, J Stary, J Trka, E Fronkova
Minimal residual disease (MRD) monitoring via quantitative PCR (qPCR) detection of Ag receptor gene rearrangements has been the most sensitive method for predicting prognosis and making post-transplant treatment decisions for patients with ALL. Despite the broad clinical usefulness and standardization of this method, we and others have repeatedly reported the possibility of false-positive MRD results caused by massive B-lymphocyte regeneration after stem cell transplantation (SCT). Next-generation sequencing (NGS) enables precise and sensitive detection of multiple Ag receptor rearrangements, thus providing a more specific readout compared to qPCR...
February 27, 2017: Bone Marrow Transplantation
https://www.readbyqxmd.com/read/28230291/therapeutic-potentials-of-bdnf-trkb-in-breast-cancer-current-status-and-perspectives
#16
Amir Tajbakhsh, Amin Mokhtari-Zaer, Mehdi Rezaee, Fahimeh Afzaljavan, Mehdi Rivandi, Seyed Mahdi Hassanian, Gordon A Ferns, Alireza Pasdar, Amir Avan
Brain-derived neurotrophic factor (BDNF) is a potent neurotrophic factor that has been shown to stimulate breast cancer cell growth and metastasis via tyrosine kinase receptors TrkA, TrkB and the p75(NTR) death receptor. The aberrant activation of BDNF/TrkB pathways can modulate several signaling pathways, including Akt/PI3K, Jak/STAT, NF-kB, UPAR/UPA, Wnt/β-catenin and VEGF pathways as well as the ER receptor. Several microRNAs have been identified that are involved in the modulation of BDNF/TrkB pathways...
February 23, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/28218045/the-significance-of-trk-receptors-in-pancreatic-cancer
#17
Matthew D Johnson, Brandon Stone, Bryan J Thibodeau, Andrew M Baschnagel, Sandra Galoforo, Laura E Fortier, Billie Ketelsen, Samreen Ahmed, Zakiya Kelley, Alaa Hana, Thomas G Wilson, John M Robertson, Robert P Jury, George D Wilson
This study investigated the Trk receptor family as a therapeutic target in pancreatic ductal adenocarcinoma and assessed their prognostic significance. Global gene expression analysis was investigated in prospectively collected pancreatic ductal adenocarcinomas that had either undergone neoadjuvant chemoradiation or were treated by surgery. PANC-1 and MIA-PaCa-2 cell lines were investigated to establish whether fractionated radiation altered expression of four neuroendocrine genes and whether this resulted in subsequent changes in radiosensitivity...
February 2017: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
https://www.readbyqxmd.com/read/28215306/neurotrophin-receptors-and-perineural-invasion-analyses-in-select-lineage-unrelated-cutaneous-malignancies-with-a-propensity-for-perineural-invasion
#18
N F Frydenlund, M Mahalingam
In this chapter, we parse the literature on neurotrophins that have been implicated in the pathogenesis of perineural invasion (PNI) in select lineage-unrelated malignancies. We also detail evidence linking neurotrophins and their receptors (TrkA, RET, p75NGFR, and NCAM) to the pathogenesis of PNI in desmoplastic melanoma and cutaneous squamous cell carcinoma-both malignancies with an established propensity for PNI. Lastly, the clinical potential of neurotrophins as receptors for targeted therapies is explored...
2017: Vitamins and Hormones
https://www.readbyqxmd.com/read/28215292/emergent-role-of-coronin-1a-in-neuronal-signaling
#19
M Martorella, K Barford, B Winkler, C D Deppmann
The Coronin family of proteins were first noted for their role in pathogen-host interactions and for modulating actin dynamics. Recently, however, Coronins have been found in a greater variety of cell types, and novel roles for the Coronins within the nervous system have been discovered. In the immune system, Coronin-1a enables Mycobacterium tuberculosis to evade lysosomal destruction. This activity appears to be analogous to protection of the NGF-TrkA signaling endosome during sympathetic nervous system development that is required for survival signaling...
2017: Vitamins and Hormones
https://www.readbyqxmd.com/read/28215291/crystal-structures-of-neurotrophin-receptors-kinase-domain
#20
T Bertrand
Neurotrophins and their receptors (Trk) play key roles in the development of the nervous system and in cell survival. Trk receptors are therefore attractive pharmacological targets for brain disorders as well as for cancers. While the druggability of the extracellular domain of the receptors, that specifically binds neurotrophins, is yet to be proven, the intracellular kinase domains are attractive targets for small-molecule binding. The recent crystal structures of the three isoforms of the Trk family, TrkA, TrkB, and TrkC have been described in their apo forms and in complex with potent and selective pan-Trk inhibitors...
2017: Vitamins and Hormones
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