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Elke Tatjana Aristizabal Prada, Vera Heinzle, Thomas Knösel, Svenja Nölting, Gerald Spoettl, Julian Maurer, Christine Spitzweg, Martin Angele, Nina Schmidt, Felix Beuschlein, Günter K Stalla, Rainer Blaser, Klaus A Kuhn, Christoph J Auernhammer
Tropomyosin receptor kinase (Trk) inhibitors are investigated as a novel targeted therapy in various cancers. We investigated the in vitro effects of the pan-Trk inhibitor GNF-5837 in human neuroendocrine tumor (NET) cells. The human neuroendocrine pancreatic BON1, bronchopulmonary NCI-H727 and ileal GOT1 cell lines were treated with GNF-5837 alone and in combination with everolimus. Cell viability decreased in a time- and dose-dependent manner in GOT1 cells in response to GNF-5837 treatment, while treatment in BON1 and NCI-H727 cells showed no effect on cellular viability...
March 21, 2018: Endocrine-related Cancer
Sarah Chiang, Paolo Cotzia, David M Hyman, Alexander Drilon, William D Tap, Lei Zhang, Jaclyn F Hechtman, Denise Frosina, Achim A Jungbluth, Rajmohan Murali, Kay J Park, Robert A Soslow, Esther Oliva, A John Iafrate, Ryma Benayed, Marc Ladanyi, Cristina R Antonescu
Tropomyosin receptor kinase (Trk) inhibitors have shown high response rates in patients with tumors harboring NTRK fusions. We identified 4 NTRK fusion-positive uterine sarcomas that should be distinguished from leiomyosarcoma and undifferentiated uterine sarcoma. NTRK rearrangements were detected by fluorescence in situ hybridization (FISH) and/or targeted RNA or DNA sequencing in 4 undifferentiated uterine sarcomas with spindle cell morphology. Because of histologic overlap with leiomyosarcoma, TrkA and pan-Trk immunohistochemistry was performed in 97 uterine leiomyosarcomas...
March 16, 2018: American Journal of Surgical Pathology
Natsumi Fujisaki, Shugo Suwazono, Masahito Suehara, Ryo Nakachi, Miwako Kido, Yoshihisa Fujiwara, Saki Oshiro, Takashi Tokashiki, Hiroshi Takashima, Masanori Nakagawa
Hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P) is a motor and sensory neuronopathy with autosomal dominant inheritance, adult onset, slowly progressive course, and is associated with TRK-fused gene (TFG) mutation. At advanced stages, respiratory failure and dysphagia becomes life-threatoning, and patients typically die by their 70s. Although there is currently no evidence for effective treatment, a therapy may be found by elucidation of the function of TFG. Recently its pathomechanism has been proposed to be associated with abnormalities in protein transfer from the endoplasmic reticulum...
February 2018: Intractable & Rare Diseases Research
Cassiano R A F Diniz, Plinio C Casarotto, Senem M Fred, Caroline Biojone, Eero Castrén, Sâmia R L Joca
The renin-angiotensin system (RAS) is associated with peripheral fluid homeostasis and cardiovascular function, but recent evidence also suggests a functional role in the brain. RAS regulates physiological and behavioral parameters related to the stress response, including depressive symptoms. Apparently, RAS can modulate levels of brain-derived neurotrophic factor (BDNF) and TRKB, which are important in the neurobiology of depression and antidepressant action. However, the interaction between the BDNF/TRKB system and RAS in depression has not been investigated before...
March 14, 2018: Neuropharmacology
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
Peter Sidaway
No abstract text is available yet for this article.
March 13, 2018: Nature Reviews. Clinical Oncology
Talha Khan Burki
No abstract text is available yet for this article.
March 1, 2018: Lancet Oncology
Tiffany M Zarrella, Dennis W Metzger, Guangchun Bai
Cyclic di-adenosine monophosphate (c-di-AMP) is a newly discovered bacterial second messenger. However, regulation of c-di-AMP homeostasis is poorly understood. In Streptococcus pneumoniae , a sole diadenylate cyclase, CdaA, produces c-di-AMP and two phosphodiesterases, Pde1 and Pde2, cleave the signaling di-nucleotide. To expand our knowledge of the pneumococcal c-di-AMP signaling network, we performed whole genome sequencing of Δ pde1 Δ pde2 heat shock suppressors. In addition to surviving heat shock, these suppressor mutants restored general stress resistance and improved growth in rich medium...
February 26, 2018: Journal of Bacteriology
Alexander Drilon, Theodore W Laetsch, Shivaani Kummar, Steven G DuBois, Ulrik N Lassen, George D Demetri, Michael Nathenson, Robert C Doebele, Anna F Farago, Alberto S Pappo, Brian Turpin, Afshin Dowlati, Marcia S Brose, Leo Mascarenhas, Noah Federman, Jordan Berlin, Wafik S El-Deiry, Christina Baik, John Deeken, Valentina Boni, Ramamoorthy Nagasubramanian, Matthew Taylor, Erin R Rudzinski, Funda Meric-Bernstam, Davendra P S Sohal, Patrick C Ma, Luis E Raez, Jaclyn F Hechtman, Ryma Benayed, Marc Ladanyi, Brian B Tuch, Kevin Ebata, Scott Cruickshank, Nora C Ku, Michael C Cox, Douglas S Hawkins, David S Hong, David M Hyman
BACKGROUND: Fusions involving one of three tropomyosin receptor kinases (TRK) occur in diverse cancers in children and adults. We evaluated the efficacy and safety of larotrectinib, a highly selective TRK inhibitor, in adults and children who had tumors with these fusions. METHODS: We enrolled patients with consecutively and prospectively identified TRK fusion-positive cancers, detected by molecular profiling as routinely performed at each site, into one of three protocols: a phase 1 study involving adults, a phase 1-2 study involving children, or a phase 2 study involving adolescents and adults...
February 22, 2018: New England Journal of Medicine
Akihiro Nishiyama, Tadaaki Yamada, Kenji Kita, Rong Wang, Sachiko Arai, Koji Fukuda, Azusa Tanimoto, Shinji Takeuchi, Shoichiro Tange, Atsushi Tajima, Noritaka Furuya, Takayoshi Kinoshita, Seiji Yano
BACKGROUND: Rearrangement of the neurotrophic tropomyosin receptor kinase 1 ( NTRK1 ) gene, which encodes tyrosine receptor kinase A (TRK-A), occurs in various cancers, including colon cancer. Although entrectinib is effective in the treatment of central nervous system (CNS) metastases that express NTRK1 fusion proteins, acquired resistance inevitably results in recurrence. CNS is a sanctuary for targeted drugs; however, the mechanism by which CNS metastases become entrectinib-resistant remains elusive and must be clarified to develop better therapeutics...
February 20, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
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...
February 17, 2018: CNS Neuroscience & Therapeutics
Manoj Kumar Pandre, Shama Shaik, V V V Satya Pratap, Prasad Yadlapalli, Mahesh Yanamandra, Sayan Mitra
Tropomyosin-related kinase A (TRKA) fusion was originally detected in colorectal carcinoma that had resulted in expression of the oncogenic chimeric protein TPM3-TRKA. Lately, many more rearrangements in TRK family of kinases generating oncogenic fusion proteins have been identified. These genetic rearrangements usually result in fusion of cytoplasmic kinase domain of TRK to another gene of interest resulting in constitutive kinase activity. Estimation of TRK inhibitor potency in a cellular context is required for drug discovery programs and is measured by receptor phosphorylation levels upon compound administration...
January 19, 2018: Analytical Biochemistry
Naoki Adachi, Shingo Suzuki, Hidetada Matsuoka, Satoko Fushimi, Junichiro Ono, Ken-Ichi Ohta, Yohei Hirai, Takanori Miki, Hisatsugu Koshimizu
A recent study revealed that corticotropin-releasing hormone (CRH) in the cerebral cortex (CTX) plays a regulatory role in emotional behaviors in rodents. Given the functional interaction between brain-derived neurotrophic factor (BDNF) and the CRH-signaling pathway in the hypothalamic-pituitary-adrenal (HPA) axis, we hypothesized that BDNF may regulate gene expression of CRH and its related molecules in the CTX. Findings of real-time quantitative PCR (RT-qPCR) indicated that stimulation of cultured rat cortical neurons with BDNF led to marked elevations in the mRNA levels of CRH and CRH-binding protein (CRH-BP)...
January 22, 2018: Journal of Neurochemistry
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
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
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...
January 8, 2018: Cancer Cell
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
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
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
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...
February 2018: Biomaterials
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