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Kazuo Nakajima, An-A Kazuno, John Kelsoe, Moe Nakanishi, Toru Takumi, Tadafumi Kato
Knockin (KI) mouse carrying a point mutation has been an invaluable tool for disease modeling and analysis. Genome editing technologies using the CRISPR/Cas system has emerged as an alternative way to create KI mice. However, if the mice carry nucleotide insertions and/or deletions (InDels) in other genes, which could have unintentionally occurred during the establishment of the KI mouse line and potentially have larger impact than a point mutation, it would confound phenotyping of the KI mice. In this study, we performed whole exome sequencing of multiple lines of F1 heterozygous Ntrk1 KI mice generated using the CRISPR/Cas system in comparison to that of a wild-type mouse used as a control...
October 4, 2016: Scientific Reports
Samiha S Shaikh, Ya-Chun Chen, Sally-Anne Halsall, Michael S Nahorski, Kiyoyuki Omoto, Gareth T Young, Anne Phelan, Christopher Geoffrey Woods
Hereditary sensory and autonomic neuropathy type IV (HSAN IV) is an autosomal recessive disorder characterized by a complete lack of pain perception and anhidrosis. Here, we studied a cohort of seven patients with HSAN IV and describe a comprehensive functional analysis of seven novel NTRK1 missense mutations, c.1550G>A, c.1565G>A, c.1970T>C, c.2096T>C, c.2254T>A, c.2288G>C, c.2311C>T, corresponding to p.G517E, p.G522E, p.L657P, p.I699T, p.C752S, p.C763S and p.R771C, all of which were predicted pathogenic by in-silico analysis...
September 27, 2016: Human Mutation
Chiara Cremolini, Filippo Pietrantonio
In metastatic colorectal cancer, the optimization of upfront treatment and the continuum of care based on patients' exposure to multiple treatment lines have reached a plateau of efficacy. Therefore, a paradigm shift is ongoing towards precision medicine and personalized treatments based on the specific molecular features of the disease. In this perspective, the improved knowledge of disease biology coming from the lab has prompted a rapid translation from bench to bedside of newer targeted strategies. Here, we focus on the most promising biomarkers already included or close to adoption in daily clinical practice...
September 20, 2016: Tumori
Sarah S Pinney, Richard R Jahan-Tigh, Susan Chon
Non-Langerhans cell histiocytosis (NLCH) is a histiocyte disorder comprised of dermal dendritic histiocytes with a characteristic staining pattern. Erdheim-Chester disease (ECD) is a subset of NLCH in which patients experience bone pain with corresponding changes on imaging. In addition, these patients show other evidence of systemic involvement, which can also be identified with imaging. This disease can occasionally present with cutaneous findings. We present a case of generalized eruptive histiocytosis (GEH), misdiagnosed as ECD, found to have an NTRK1 gene rearrangement...
2016: Dermatology Online Journal
María Luisa Franco, Cristina Melero, Esther Sarasola, Paloma Acebo, Alfonso Luque, Isabel Calatayud-Baselga, María García-Barcina, Marçal Vilar
Congenital insensitivity to pain with anhidrosis (CIPA) is a rare autosomal recessive disorder characterized by insensitivity to noxious stimuli and variable intellectual disability (ID) due to mutations in the NTRK1 gene encoding the NGF receptor TrkA. To get an insight in the effect of NTRK1 mutations in the cognitive phenotype we biochemically characterized three TrkA mutations identified in children diagnosed of CIPA with variable ID. These mutations are located in different domains of the protein; L213P in the extracellular domain, Δ736 in the kinase domain and C300stop in the extracellular domain, a new mutation causing CIPA diagnosed in a Spanish teenager...
August 22, 2016: Journal of Biological Chemistry
Wei Chen, Bing-Yao Liu, Xiang Zhang, Xiao-Ge Zhao, Gang Cao, Zhen Dong, Sen-Lin Zhang
INTRODUCTION: Salivary adenoid cystic carcinoma (SACC) is a frequent type of salivary gland cancer which is characterized by slow growth but high incidence of distant metastasis. We aimed to identify therapeutic targets which are associated with metastasis of SACC. MATERIAL AND METHODS: Total RNA was isolated from a low metastatic SACC cell line (ACC-2) and a highly metastatic SACC cell line (ACC-M), which was screened from ACC-2 by combination of in vivo selection and cloning in vitro...
August 1, 2016: Archives of Medical Science: AMS
Iwei Yeh, Meng Kian Tee, Thomas Botton, A Hunter Shain, Alyssa J Sparatta, Alexander Gagnon, Swapna S Vemula, Maria C Garrido, Kenji Nakamaru, Takeshi Isoyama, Timothy H McCalmont, Philip E LeBoit, Boris C Bastian
Oncogenic fusions in TRK family receptor tyrosine kinases have been identified in several cancers and can serve as therapeutic targets. We identified ETV6-NTRK3, MYO5A-NTRK3 and MYH9-NTRK3 fusions in Spitz tumours and demonstrate that NTRK3 fusions constitutively activate the MAPK, PI3K and PLCγ1 pathways in melanocytes. This signalling was inhibited by DS-6051a, a small molecule inhibitor of NTRK1/2/3 and ROS1. NTRK3 fusions expand the range of oncogenic kinase fusions in melanocytic neoplasms and offer targets for a small subset of melanomas for which currently no targeted options exist...
August 1, 2016: Journal of Pathology
Senthilvelan Manohar, Kimberly Dahar, Henry J Adler, Ding Dalian, Richard Salvi
Severe noise-induced damage to the inner ear leads to auditory nerve fiber degeneration thereby reducing the neural input to the cochlear nucleus (CN). Paradoxically, this leads to a significant increase in spontaneous activity in the CN which has been linked to tinnitus, hyperacusis and ear pain. The biological mechanisms that lead to an increased spontaneous activity are largely unknown, but could arise from changes in glutamatergic or GABAergic neurotransmission or neuroinflammation. To test this hypothesis, we unilaterally exposed rats for 2h to a 126dB SPL narrow band noise centered at 12kHz...
September 2016: Molecular and Cellular Neurosciences
Francesco Facchinetti, Marcello Tiseo, Massimo Di Maio, Paolo Graziano, Emilio Bria, Giulio Rossi, Silvia Novello
Crizotinib is an oral inhibitor of anaplastic lymphoma kinase (ALK) with remarkable clinical activity in patients suffering from ALK-rearranged non-small cell lung cancer (NSCLC), accounting to its superiority compared to chemotherapy. Unfortunately, virtually all ALK-rearranged tumors acquire resistance to crizotinib, frequently within one year since the treatment initiation. To date, therapeutic strategies to overcome crizotinib resistance have focused on the use of more potent and structurally different compounds...
June 2016: Translational Lung Cancer Research
Christina Y Lee, Lauren M Sholl, Bin Zhang, Emily A Merkel, Sapna M Amin, Joan Guitart, Pedram Gerami
The natural history of atypical Spitz neoplasms remains poorly understood, resulting in significant patient and clinician anxiety. We sought to better characterize outcomes that correlated with molecular features by performing a prospective cohort study of pediatric atypical spitzoid neoplasms in which fluorescence in situ hybridization studies were obtained for diagnosis. Cases with sufficient tissue underwent additional retrospective assessment for translocations in ALK, NTRK1, BRAF, RET, and ROS1. Among 246 total patients assessed, 13% had a positive fluorescence in situ hybridization result...
July 7, 2016: American Journal of Dermatopathology
Curtis R Chong, Magda Bahcall, Marzia Capelletti, Takayuki Kosaka, Dalia Ercan, Taebo Sim, Lynette M Sholl, Mizuki Nishino, Bruce E Johnson, Nathanael S Gray, Pasi A Janne
PURPOSE: Efforts to discover drugs that overcome resistance to targeted therapies in patients with rare oncogenic alterations, such as NTRK1- and ROS1-rearrangements, are complicated by the cost and protracted timeline of drug discovery. EXPERIMENTAL DESIGN: In an effort to identify inhibitors of NTRK1 and ROS1, which are aberrantly activated in some patients with non-small cell lung cancer (NSCLC), we created and screened a library of existing targeted drugs against Ba/F3 cells transformed with these oncogenes...
July 1, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Masakuni Serizawa, Masatoshi Kusuhara, Sumiko Ohnami, Takeshi Nagashima, Yuji Shimoda, Keiichi Ohshima, Tohru Mochizuki, Kenichi Urakami, Ken Yamaguchi
BACKGROUND/AIM: The identification of additional therapeutic targets by clinical molecular profiling is necessary to expand the range of molecular-targeted cancer therapeutics. This study aimed to identify novel functional tumor-specific single nucleotide variants (SNVs) in the kinase domain of receptor tyrosine kinases (RTKs), from whole-exome sequencing (WES) data. MATERIALS AND METHODS: SNVs were selected from WES data of multiple cancer types using both cancer-related databases and the index reflecting molecular evolution...
June 2016: Anticancer Research
Qing-Li Wang, Shanna Guo, Guangyou Duan, Ying Ying, Penghao Huang, Jing Yu Liu, Xianwei Zhang
BACKGROUND: Congenital insensitivity to pain with anhidrosis is an extremely rare hereditary disorder linked to variants in NTRK1. Our goal was to characterize the clinical features and the genetic basis of the disorder in Chinese patients. METHODS: Patients were enrolled via social networking. Clinical features were investigated by interview, chart review, and physical examination. DNA was extracted from peripheral blood to genotype NTRK1 in patients and their parents...
August 2016: Pediatric Neurology
Narasimhan P Agaram, Lei Zhang, Yun-Shao Sung, Chun-Liang Chen, Catherine T Chung, Cristina R Antonescu, Christopher Dm Fletcher
The family of pediatric fibroblastic and myofibroblastic proliferations encompasses a wide spectrum of pathologic entities with overlapping morphologies and ill-defined genetic abnormalities. Among the superficial lesions, lipofibromatosis (LPF), composed of an admixture of adipose tissue and fibroblastic elements, in the past has been variously classified as infantile fibromatosis or fibrous hamartoma of infancy. In this regard, we have encountered a group of superficial soft tissue tumors occurring in children and young adults, with a notably infiltrative growth pattern reminiscent of LPF, variable cytologic atypia, and a distinct immunoprofile of S100 protein and CD34 reactivity, suggestive of neural differentiation...
October 2016: American Journal of Surgical Pathology
Sarah Keppler, Susann Weiβbach, Christian Langer, Stefan Knop, Jordan Pischimarov, Miriam Kull, Thorsten Stühmer, Torsten Steinbrunn, Ralf Bargou, Hermann Einsele, Andreas Rosenwald, Ellen Leich
Multiple myeloma (MM) is a plasma cell disorder that is characterized by a great genetic heterogeneity. Recent next generation sequencing studies revealed an accumulation of tumor-associated mutations in receptor tyrosine kinases (RTKs) which may also contribute to the activation of survival pathways in MM. To investigate the clinical role of RTK-mutations in MM, we deep-sequenced the coding DNA-sequence of EGFR, EPHA2, ERBB3, IGF1R, NTRK1 and NTRK2 which were previously found to be mutated in MM, in 75 uniformly treated MM patients of the "Deutsche Studiengruppe Multiples Myelom"...
May 26, 2016: Oncotarget
Ingo Kurth, Manuela Baumgartner, Maria Schabhüttl, Cecilia Tomni, Reinhard Windhager, Tim M Strom, Thomas Wieland, Kurt Gremel, Michaela Auer-Grumbach
Congenital insensitivity to pain and anhidrosis (CIPA), also known as hereditary sensory and autonomic neuropathy type IV (HSAN IV), is characterized by recurrent episodes of unexplained high fever, loss of pain perception and temperature sensation, absent sweating, repeated traumatic and thermal injuries, and mild mental retardation. After exclusion of obviously pathogenic mutations in NTRK1, the most common cause of CIPA, whole exome sequencing (WES) was carried out in a CIPA patient with unrelated parents...
September 2016: American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics
James H Suh, Adrienne Johnson, Lee Albacker, Kai Wang, Juliann Chmielecki, Garrett Frampton, Laurie Gay, Julia A Elvin, Jo-Anne Vergilio, Siraj Ali, Vincent A Miller, Philip J Stephens, Jeffrey S Ross
BACKGROUND: The National Comprehensive Cancer Network (NCCN) guidelines for patients with metastatic non-small cell lung cancer (NSCLC) recommend testing for EGFR, BRAF, ERBB2, and MET mutations; ALK, ROS1, and RET rearrangements; and MET amplification. We investigated the feasibility and utility of comprehensive genomic profiling (CGP), a hybrid capture-based next-generation sequencing (NGS) test, in clinical practice. METHODS: CGP was performed to a mean coverage depth of 576× on 6,832 consecutive cases of NSCLC (2012-2015)...
June 2016: Oncologist
(no author information available yet)
LOXO-101, which targets proteins encoded by gene fusions involving NTRK1, NTRK2, and NTRK3, and entrectinib, which targets fusion proteins encoded by translocations in ROS1 and ALK, yielded dramatic clinical activity in patients with a variety of cancers in separate phase I trials. The data were presented at the American Association for Cancer Research Annual Meeting 2016, April 16-20, in New Orleans, LA.
June 2016: Cancer Discovery
Danielle A Murphy, Heather A Ely, Robert Shoemaker, Aaron Boomer, Brady P Culver, Ian Hoskins, Josh D Haimes, Ryan D Walters, Diane Fernandez, Joshua A Stahl, Jeeyun Lee, Kyoung-Mee Kim, Jennifer Lamoureux, Jason Christiansen
Targeted therapy combined with companion diagnostics has led to the advancement of next-generation sequencing (NGS) for detection of molecular alterations. However, using a diagnostic test to identify patient populations with low prevalence molecular alterations, such as gene rearrangements, poses efficiency, and cost challenges. To address this, we have developed a 2-step diagnostic test to identify NTRK1, NTRK2, NTRK3, ROS1, and ALK rearrangements in formalin-fixed paraffin-embedded clinical specimens. This test is comprised of immunohistochemistry screening using a pan-receptor tyrosine kinase cocktail of antibodies to identify samples expressing TrkA (encoded by NTRK1), TrkB (encoded by NTRK2), TrkC (encoded by NTRK3), ROS1, and ALK followed by an RNA-based anchored multiplex polymerase chain reaction NGS assay...
March 29, 2016: Applied Immunohistochemistry & Molecular Morphology: AIMM
Thomas Wiesner, Heinz Kutzner, Lorenzo Cerroni, Martin C Mihm, Klaus J Busam, Rajmohan Murali
Histopathological evaluation of melanocytic tumours usually allows reliable distinction of benign melanocytic naevi from melanoma. More difficult is the histopathological classification of Spitz tumours, a heterogeneous group of tumours composed of large epithelioid or spindle-shaped melanocytes. Spitz tumours are biologically distinct from conventional melanocytic naevi and melanoma, as exemplified by their distinct patterns of genetic aberrations. Whereas common acquired naevi and melanoma often harbour BRAF mutations, NRAS mutations, or inactivation of NF1, Spitz tumours show HRAS mutations, inactivation of BAP1 (often combined with BRAF mutations), or genomic rearrangements involving the kinases ALK, ROS1, NTRK1, BRAF, RET, and MET...
February 2016: Pathology
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