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https://www.readbyqxmd.com/read/29125233/in-vivo-imaging-xenograft-models-for-the-evaluation-of-anti-brain-tumor-efficacy-of-targeted-drugs
#1
Kenji Kita, Sachiko Arai, Akihiro Nishiyama, Hirokazu Taniguchi, Koji Fukuda, Rong Wang, Tadaaki Yamada, Shinji Takeuchi, Shoichiro Tange, Atsushi Tajima, Mitsutoshi Nakada, Kazuo Yasumoto, Yoshiharu Motoo, Takashi Murakami, Seiji Yano
Molecular-targeted drugs are generally effective against tumors containing driver oncogenes, such as EGFR, ALK, and NTRK1. However, patients harboring these oncogenes frequently experience a progression of brain metastases during treatment. Here, we present an in vivo imaging model for brain tumors using human cancer cell lines, including the EGFR-L858R/T790M-positive H1975 lung adenocarcinoma cells, the NUGC4 hepatocyte growth factor (HGF)-dependent gastric cancer cells, and the KM12SM colorectal cancer cells containing the TPM3-NTRK1 gene fusion...
November 10, 2017: Cancer Medicine
https://www.readbyqxmd.com/read/29118225/activity-of-entrectinib-in-a-patient-with-the-first-reported-ntrk-fusion-in-neuroendocrine-cancer
#2
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/29054434/associations-between-single-nucleotide-polymorphisms-in-the-ntrk1-gene-and-basal-pain-sensitivity-in-young-han-chinese-women
#3
Ningbo Li, Guangyou Duan, Jiaoli Sun, Shanna Guo, Qingli Wang, Hua Zheng, Cong Wang, Changmao Zhu, Yi Liu, Xianwei Zhang
OBJECTIVES: The NTRK1 gene plays an important role in sensory and sympathetic neuronal survival. Mutations in this gene cause a rare hereditary disease known as congenital insensitivity to pain with anhidrosis. The aim of this study was to explore possible associations between single-nucleotide polymorphisms (SNPs) in NTRK1 and pain perception in a selected population. METHODS: A total of 309 healthy Han Chinese female undergraduates were recruited. Responses to quantitative sensory testing of pressure pain (dull, sharp, and acupuncture) were assessed, and genotyping of 13 tag-SNPs of NTRK1 was performed in the undergraduates recruited...
October 18, 2017: Neuroscience Letters
https://www.readbyqxmd.com/read/29046324/etv6-ntrk3-and-strn-alk-kinases-fusions-are-recurrent-events-in-papillary-thyroid-cancer-of-adult-population
#4
André U Bastos, Ana Carolina de Jesus, Janete Maria Cerutti
OBJECTIVE: PTC-specific analysis identified novel fusions involving RET, BRAF, NTRK1, NTRK3, AGK and ALK genes in adults and pediatric PTC. Although many novel fusions are PTC-specific event and, therefore, are ideal for diagnosis purposes, validation across additional and larger cohorts is essential for introducing these potential diagnostic or prognostic biomarkers into the clinical practice. As most of the BRAF, NTRK3 and ALK fusions were initially found in pediatric PTC or in more aggressive thyroid carcinomas, and there is a great disparity across population, in this study, we screened a large set of adult sporadic PTC cases for the most prevalent kinases fusion lately described in the TCGA...
October 18, 2017: European Journal of Endocrinology
https://www.readbyqxmd.com/read/29045518/negative-hyper-selection-of-metastatic-colorectal-cancer-patients-for-anti-egfr-monoclonal-antibodies-the-pressing-case-control-study
#5
C Cremolini, F Morano, R Moretto, R Berenato, E Tamborini, F Perrone, D Rossini, A Gloghini, A Busico, G Zucchelli, C Baratelli, E Tamburini, M Tampellini, E Sensi, G Fucà, C Volpi, M Milione, M Di Maio, G Fontanini, F De Braud, A Falcone, F Pietrantonio
Background: Refining the selection of metastatic colorectal cancer (mCRC) patients candidates for anti-EGFR monoclonal antibodies beyond RAS and BRAF testing is a challenge of precision oncology. Several uncommon genomic mechanisms of primary resistance, leading to activation of tyrosine kinase receptors other than EGFR or downstream signaling pathways, have been suggested by preclinical and retrospective studies. Patients and methods: We conducted this multicenter, prospective, case-control study to demonstrate the negative predictive impact of a panel of rare genomic alterations (PRESSING panel), including HER2/MET amplifications, ALK/ROS1/NTRK1-3/RET fusions, and HER2/PI3K/PTEN/AKT1 mutations...
September 25, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/29037860/neurotrophin-receptors-trka-p75-ntr-and-sortilin-are-increased-and-targetable-in-thyroid-cancer
#6
Sam Faulkner, Philip Jobling, Christopher Rowe, Sonia Rodriguez-Oliveira, Severine Roselli, Rick Thorne, Christopher Oldmeadow, John Attia, Chen Chen Jiang, Xu Dong Zhang, Marjorie M Walker, Hubert Hondermarck
Neurotrophin receptors are emerging targets in oncology, but their clinicopathologic significance in thyroid cancer is unclear. In this study, the neurotrophin tyrosine receptor kinase TrkA (also called NTRK1), the common neurotrophin receptor p75(NTR), and the proneurotrophin receptor sortilin were analyzed with immunohistochemistry in a cohort of thyroid cancers (n = 128) and compared with adenomas and normal thyroid tissues (n = 62). TrkA was detected in 20% of thyroid cancers, compared with none of the benign samples (P = 0...
October 14, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28981924/-mutation-analysis-of-ntrk1-gene-in-a-family-affected-with-congenital-insensitivity-to-pain-with-anhidrosis
#7
Bingxiao Li, Zhanhui Zhang, Xia Wu, Wenchao Chen, Jianling Chen, Qian Lyu, Guosheng Liu
OBJECTIVE: To screen for mutations of NTRK1 gene in a Chinese family affected with congenital insensitivity to pain with anhidrosis (CIPA). METHODS: Genomic DNA was extracted from the proband and her family members. All of the 17 exons and intron-exon boundaries of the NTRK1 gene were analyzed by direct Sanger sequencing. For the deletional mutation, the PCR products were subjected to T-A cloning and sequencing to verify the mutation. RESULTS: NTRK1 gene analysis revealed that proband has carried a c...
October 10, 2017: Zhonghua Yi Xue Yi Chuan Xue za Zhi, Zhonghua Yixue Yichuanxue Zazhi, Chinese Journal of Medical Genetics
https://www.readbyqxmd.com/read/28903424/identification-and-characterization-of-a-novel-scyl3-ntrk1-rearrangement-in-a-colorectal-cancer-patient
#8
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/28877062/recurrent-braf-gene-fusions-in-a-subset-of-pediatric-spindle-cell-sarcomas-expanding-the-genetic-spectrum-of-tumors-with-overlapping-features-with-infantile-fibrosarcoma
#9
Yu-Chien Kao, Christopher D M Fletcher, Rita Alaggio, Leonard Wexler, Lei Zhang, Yun-Shao Sung, Dicle Orhan, Wei-Chin Chang, David Swanson, Brendan C Dickson, Cristina R Antonescu
Infantile fibrosarcomas (IFS) represent a distinct group of soft tissue tumors occurring in patients under 2 years of age and most commonly involving the extremities. Most IFS show recurrent ETV6-NTRK3 gene fusions, sensitivity to chemotherapy, and an overall favorable clinical outcome. However, outside these well-defined pathologic features, no studies have investigated IFS lacking ETV6-NTRK3 fusions, or tumors with the morphology resembling IFS in older children. This study was triggered by the identification of a novel SEPT7-BRAF fusion in an unclassified retroperitoneal spindle cell sarcoma in a 16-year-old female by targeted RNA sequencing...
September 4, 2017: American Journal of Surgical Pathology
https://www.readbyqxmd.com/read/28857077/fusions-in-solid-tumours-diagnostic-strategies-targeted-therapy-and-acquired-resistance
#10
REVIEW
Alison M Schram, Matthew T Chang, Philip Jonsson, Alexander Drilon
Structural gene rearrangements resulting in gene fusions are frequent events in solid tumours. The identification of certain activating fusions can aid in the diagnosis and effective treatment of patients with tumours harbouring these alterations. Advances in the techniques used to identify fusions have enabled physicians to detect these alterations in the clinic. Targeted therapies directed at constitutively activated oncogenic tyrosine kinases have proven remarkably effective against cancers with fusions involving ALK, ROS1, or PDGFB, and the efficacy of this approach continues to be explored in malignancies with RET, NTRK1/2/3, FGFR1/2/3, and BRAF/CRAF fusions...
August 31, 2017: Nature Reviews. Clinical Oncology
https://www.readbyqxmd.com/read/28851664/pediatric-soft-tissue-tumor-of-the-upper-arm-with-lmna-ntrk1-fusion
#11
Shinji Kohsaka, Tsuyoshi Saito, Keisuke Akaike, Yoshiyuki Suehara, Takuo Hayashi, Tatsuya Takagi, Kazuo Kaneko, Toshihide Ueno, Shinya Kojima, Ken-Ichi Kohashi, Hiroyuki Mano, Yoshinao Oda, Takashi Yao
A 6-year-old girl was admitted to our hospital due to the presence of a slow-growing tumor in her right elbow. Biopsy specimens showed a round- to spindle-cell neoplasm with uncertain malignant potential, leading to the decision of surgical resection. Histologically, the resected tumor was encapsulated by fibrous tissue, but focally invaded the surrounding skeletal muscles. The tumor was composed of ganglion-cell-like short spindle cells with lymphocytic infiltration in the collagenous background. Tumor cells with large bizarre nuclei were occasionally observed, and multinucleated giant cells were scattered at the periphery...
August 26, 2017: Human Pathology
https://www.readbyqxmd.com/read/28802494/toward-a-molecular-genetic-classification-of-spitzoid-neoplasms
#12
REVIEW
Michael T Tetzlaff, Alexandre Reuben, Steven D Billings, Victor G Prieto, Jonathan L Curry
The histopathologic spectrum of Spitzoid neoplasms includes Spitz nevi, atypical Spitz tumors, and Spitzoid melanomas. Advances in molecular genetics have evolved to the point that Spitzoid lesions can now be reasonably classified according to their distinctive molecular-genetic alterations: Spitzoid lesions with (1) 11p amplification and/or HRAS mutations; (2) isolated loss of 6q23 by fluorescence in situ hybridization (FISH); (3) homozygous deletion of 9p21 by FISH; (4) BAP1 loss and BRAFV600 E mutation; (5) translocations involving any of a number of different oncogenic kinase drivers, including ROS1, ALK, NTRK1, NTRK3, MET, BRAF, and RET; and (6) TERT promoter mutations...
September 2017: Clinics in Laboratory Medicine
https://www.readbyqxmd.com/read/28767387/identification-and-characterization-of-a-novel-scyl3-ntrk1-rearrangement-in-a-colorectal-cancer-patient
#13
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/28751539/mechanisms-of-resistance-to-ntrk-inhibitors-and-therapeutic-strategies-in-ntrk1-rearranged-cancers
#14
Miho J Fuse, Koutaroh Okada, Tomoko Oh-Hara, Hayato Ogura, Naoya Fujita, Ryohei Katayama
Neurotrophic receptor tyrosine kinase 1 (NTRK1) gene rearrangement leads to constitutive activation of NTRK1, which induces high transforming ability. NTRK-rearranged cancers have been identified in several cancer types, such as glioblastoma, non-small-cell lung cancer, and colorectal cancer. Although there are currently no clinically approved inhibitors that target NTRK1, several tyrosine kinase inhibitors (TKIs), such as entrectinib and LOXO-101, are in clinical trials. The purpose of this study was to identify potential mechanisms of resistance to NTRK inhibitors and find potential therapeutic strategies to overcome the resistance...
July 27, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28719467/pan-trk-immunohistochemistry-is-an-efficient-and-reliable-screen-for-the-detection-of-ntrk-fusions
#15
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
https://www.readbyqxmd.com/read/28696690/a-kinome-wide-selective-radiolabeled-trkb-c-inhibitor-for-in-vitro-and-in-vivo-neuroimaging-synthesis-preclinical-evaluation-and-first-in-human
#16
Vadim Bernard-Gauthier, Justin J Bailey, Andrew V Mossine, Simon Lindner, Lena Vomacka, Arturo Aliaga, Xia Shao, Carole A Quesada, Phillip Sherman, Anne Mahringer, Alexey Kostikov, Marilyn Grand'Maison, Pedro Rosa-Neto, Jean-Paul Soucy, Alexander Thiel, David R Kaplan, Gert Fricker, Björn Wängler, Peter Bartenstein, Ralf Schirrmacher, Peter J H Scott
The proto-oncogenes NTRK1/2/3 encode the tropomyosin receptor kinases TrkA/B/C which play pivotal roles in neurobiology and cancer. We describe herein the discovery of [(11)C]-(R)-3 ([(11)C]-(R)-IPMICF16), a first-in-class positron emission tomography (PET) TrkB/C-targeting radiolabeled kinase inhibitor lead. Relying on extensive human kinome vetting, we show that (R)-3 is the most potent and most selective TrkB/C inhibitor characterized to date. It is demonstrated that [(11)C]-(R)-3 readily crosses the blood-brain barrier (BBB) in rodents and selectively binds to TrkB/C receptors in vivo, as evidenced by entrectinib blocking studies...
August 24, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28695888/somatic-chromosomal-engineering-identifies-bcan-ntrk1-as-a-potent-glioma-driver-and-therapeutic-target
#17
Peter J Cook, Rozario Thomas, Ram Kannan, Esther Sanchez de Leon, Alexander Drilon, Marc K Rosenblum, Maurizio Scaltriti, Robert Benezra, Andrea Ventura
The widespread application of high-throughput sequencing methods is resulting in the identification of a rapidly growing number of novel gene fusions caused by tumour-specific chromosomal rearrangements, whose oncogenic potential remains unknown. Here we describe a strategy that builds upon recent advances in genome editing and combines ex vivo and in vivo chromosomal engineering to rapidly and effectively interrogate the oncogenic potential of genomic rearrangements identified in human brain cancers. We show that one such rearrangement, an microdeletion resulting in a fusion between Brevican (BCAN) and Neurotrophic Receptor Tyrosine Kinase 1 (NTRK1), is a potent oncogenic driver of high-grade gliomas and confers sensitivity to the experimental TRK inhibitor entrectinib...
July 11, 2017: Nature Communications
https://www.readbyqxmd.com/read/28683589/infantile-ntrk-associated-mesenchymal-tumors
#18
Jessica L Davis, Christina M Lockwood, Catherine M Albert, Karen Tsuchiya, Douglas S Hawkins, Erin R Rudzinski
Pediatric fibroblastic/myofibroblastic lesions are a relatively common group of tumors with varying morphologies, for which the molecular mechanisms are becoming increasingly well characterized. Congenital infantile fibrosarcoma (CIFS), perhaps the most well studied of these lesions is characterized by a recurrent ETV6-NTRK3 gene fusion. However, a notable subset of locally aggressive congenital/infantile soft tissue lesions with similar morphologic features to CIFS, have not to-date, shown evidence of any canonical molecular aberration...
January 1, 2017: Pediatric and Developmental Pathology
https://www.readbyqxmd.com/read/28591715/brca2-egfr-and-ntrk-mutations-in-mismatch-repair-deficient-colorectal-cancers-with-msh2-or-mlh1-mutations
#19
Safoora Deihimi, Avital Lev, Michael Slifker, Elena Shagisultanova, Qifang Xu, Kyungsuk Jung, Namrata Vijayvergia, Eric A Ross, Joanne Xiu, Jeffrey Swensen, Zoran Gatalica, Mark Andrake, Roland L Dunbrack, Wafik S El-Deiry
Deficient mismatch repair (MMR) and microsatellite instability (MSI) contribute to ~15% of colorectal cancer (CRCs). We hypothesized MSI leads to mutations in DNA repair proteins including BRCA2 and cancer drivers including EGFR. We analyzed mutations among a discovery cohort of 26 MSI-High (MSI-H) and 558 non-MSI-H CRCs profiled at Caris Life Sciences. Caris-profiled MSI-H CRCs had high mutation rates (50% vs 14% in non-MSI-H, P < 0.0001) in BRCA2. Of 1104 profiled CRCs from a second cohort (COSMIC), MSH2/MLH1-mutant CRCs showed higher mutation rates in BRCA2 compared to non-MSH2/MLH1-mutant tumors (38% vs 6%, P < 0...
June 20, 2017: Oncotarget
https://www.readbyqxmd.com/read/28590426/down-s-syndrome-and-triple-negative-breast-cancer-a-rare-occurrence-of-distinctive-clinical-relationship
#20
Nandini Dey, Amy Krie, Jessica Klein, Kirstin Williams, Amanda McMillan, Rachel Elsey, Yuliang Sun, Casey Williams, Pradip De, Brian Leyland-Jones
Down's syndrome (DS), the most common genetic cause of significant intellectual disability in children and adults is caused by the trisomy of either all or a part of human chromosome 21 (HSA21). Patients with DS mostly suffer from characteristic tumor types. Although individual patients of DS are at a higher risk for acute leukemia and testicular cancers, other types of solid tumors including breast cancers are mostly uncommon and have significantly lower-than-expected age-adjusted incidence rates. Except for an increased risk of retinoblastomas, and lymphomas, the risk of developing solid tumors has been found to be lower in both children and adults, and breast cancer was found to be almost absent (Hasle H...
June 7, 2017: International Journal of Molecular Sciences
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