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https://www.readbyqxmd.com/read/29117359/co-occurring-genomic-alterations-and-association-with-progression-free-survival-in-brafv600-mutated-nonmelanoma-tumors
#1
Shiraj Sen, Funda Meric-Bernstam, David S Hong, Kenneth R Hess, Vivek Subbiah
BRAFV600 mutations occur in multiple nonmelanoma tumors, but no US Food and Drug Administration-approved BRAF-targeted therapies exist for these cancers. BRAF inhibitor vemurafenib was recently found to demonstrate activity across various BRAF-mutated nonmelanoma cancer types. However, most tumors ultimately become resistant to BRAF-targeted monotherapy. To identify whether co-occurring genomic alterations drive resistance to BRAF-targeted therapies, we analyzed next-generation sequencing data from 30 advanced BRAF-mutated nonmelanoma cancers treated with BRAF inhibitor monotherapy...
October 1, 2017: Journal of the National Cancer Institute
https://www.readbyqxmd.com/read/29117154/brafv600e-and-ret-ptc-promote-proliferation-and-migration-of-papillary-thyroid-carcinoma-cells-in-vitro-by-regulating-nuclear-factor-%C3%AE%C2%BAb
#2
Dehua Zhou, Zhou Li, Xuefeng Bai
BACKGROUND Papillary thyroid carcinoma (PTC) is associated with mutations of BRAFV600E and RET/PTC and high levels of expression of nuclear factor-κB (NF-κB). However, few studies have focused on the association between NF-κB expression and mutations in BRAFV600E and RET/PTC, especially regarding PTC cell proliferation and migration. The aim of this in vitro study was to investigate the effect of BRAFV600E or RET/PTC on NF-κB expression, cell proliferation and cell migration in four established PTC cell lines...
November 8, 2017: Medical Science Monitor: International Medical Journal of Experimental and Clinical Research
https://www.readbyqxmd.com/read/29115628/aberrant-hypermethylation-of-the-hoxd10-gene-in-papillary-thyroid-cancer-with-brafv600e-mutation
#3
Yi-Ming Cao, Jun Gu, Yan-Shu Zhang, Wen-Jun Wei, Ning Qu, Duo Wen, Tian Liao, Rong-Liang Shi, Ling Zhang, Qing-Hai Ji, Yu Wang, Guo-Hua Sun, Yang-Xing Zhao, Yuan-Jin Wang, Jian Yu, Yong-Xue Zhu
Epigenetic abnormalities as well as genetic abnormalities may play a vital role in the tumorigenesis of papillary thyroid cancer (PTC). The present study aimed to analyze the function and methylation status of the HOXD10 gene in PTC and aimed to identify relationships between HOXD10 methylation, HOXD10 expression, BRAF mutation and clinicopathological characteristics of PTC. A total of 152 PTC patients were enrolled in the present study. The methylation status of the HOXD10 promoter was analyzed by quantitative methylation-specific polymerase chain reaction (Q-MSP)...
October 25, 2017: Oncology Reports
https://www.readbyqxmd.com/read/29113311/the-anti-apoptotic-bag3-protein-is-involved-in-braf-inhibitor-resistance-in-melanoma-cells
#4
Luana Guerriero, Giuseppe Palmieri, Margot De Marco, Antonio Cossu, Paolo Remondelli, Mario Capunzo, Maria Caterina Turco, Alessandra Rosati
BAG3 protein, a member of BAG family of co-chaperones, has a pro-survival role in several tumour types. BAG3 anti-apoptotic properties rely on its characteristic to bind several intracellular partners, thereby modulating crucial events such as apoptosis, differentiation, cell motility, and autophagy. In human melanomas, BAG3 positivity is correlated with the aggressiveness of the tumour cells and can sustain IKK-γ levels, allowing a sustained activation of NF-κB. Furthermore, BAG3 is able to modulate BRAFV600E levels and activity in thyroid carcinomas...
October 6, 2017: Oncotarget
https://www.readbyqxmd.com/read/29096034/cns-erdheim-chester-disease-a-challenge-to-diagnose
#5
Zenggang Pan, Bette K Kleinschmidt-DeMasters
Erdheim-Chester disease (ECD) is a rare nonLangerhans cell histiocytosis. Although approximately 50% of cases eventually involve the central nervous system (CNS), the CNS has seldom been reported as the initial biopsy site. The diagnosis of CNS ECD can be challenging due to morphologic overlap with reactive histiocytic proliferation, Langerhans cell histiocytosis (LCH), and extranodal Rosai-Dorfman disease (RDD). We present 3 cases from our files that illustrate the protean manifestations of ECD. Case 1 was a 47-year-old man with ataxia, dysarthria, and intermittent ophthalmoplegia whose cerebellar biopsy had shown only profuse, nonspecific Rosenthal fiber-rich piloid gliosis; ECD was diagnosed only at autopsy...
December 1, 2017: Journal of Neuropathology and Experimental Neurology
https://www.readbyqxmd.com/read/29074620/the-natural-product-mensacarcin-induces-mitochondrial-toxicity-and-apoptosis-in-melanoma-cells
#6
Birte Plitzko, Elizabeth N Kaweesa, Sandra Loesgen
Mensacarcin is a highly oxygenated polyketide that was first isolated from soil-dwelling Streptomyces bacteria. It exhibits potent cytostatic properties (GI50: 0.2 μM) in almost all cell lines of the National Cancer Institute (NCI)-60 cell line screen and relatively selective cytotoxicity against melanoma cells. Moreover, its low COMPARE correlations with known standard antitumor agents indicate a unique mechanism of action. Effective therapies for managing melanoma are limited, so we sought to investigate mensacarcin's unique cytostatic and cytotoxic effects and its mode of action...
October 26, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29063957/significance-of-h3k27m-mutation-with-specific-histomorphological-features-and-associated-molecular-alterations-in-pediatric-high-grade-glial-tumors
#7
Süheyla Uyar Bozkurt, A Dagcinar, B Tanrikulu, N Comunoglu, B C Meydan, M Ozek, B Oz
PURPOSE: Pediatric high-grade gliomas (pHGGs) constitute almost 15% of all childhood brain tumors. Recurrent mutations such as H3K27M mutation in H3F3A and HIST1H3B genes encoding histone H3 and its variants were identified in approximately 30% of pediatric glioblastomas. This study aimed to ascertain the morphological and molecular characteristics of pHGGs with H3K27M mutation. METHODS: In total, 61 cases of pHGGs (anaplastic astrocytoma, 12; glioblastomas, 49) from four university hospitals were studied...
October 24, 2017: Child's Nervous System: ChNS: Official Journal of the International Society for Pediatric Neurosurgery
https://www.readbyqxmd.com/read/29055842/clinical-and-molecular-characterisation-of-hereditary-and-sporadic-metastatic-colorectal-cancers-harbouring-microsatellite-instability-dna-mismatch-repair-deficiency
#8
R Cohen, O Buhard, P Cervera, E Hain, S Dumont, A Bardier, J-B Bachet, J-M Gornet, D Lopez-Trabada, S Dumont, R Kaci, P Bertheau, F Renaud, F Bibeau, Y Parc, D Vernerey, A Duval, M Svrcek, Thierry André
BACKGROUND: Patients treated with chemotherapy for microsatellite unstable (MSI) and/or mismatch repair deficient (dMMR) cancer metastatic colorectal cancer (mCRC) exhibit poor prognosis. We aimed to evaluate the relevance of distinguishing sporadic from Lynch syndrome (LS)-like mCRCs. PATIENTS AND METHODS: MSI/dMMR mCRC patients were retrospectively identified in six French hospitals. Tumour samples were screened for MSI, dMMR, RAS/RAF mutations and MLH1 methylation...
October 19, 2017: European Journal of Cancer
https://www.readbyqxmd.com/read/29050198/mtorc1-autophagy-regulated-mertk-in-mutant-brafv600-melanoma-with-acquired-resistance-to-braf-inhibition
#9
Gongda Xue, Reto Kohler, Fengyuan Tang, Debby Hynx, Yuhua Wang, Francesca Orso, Vincent Prêtre, Reto Ritschard, Petra Hirschmann, Peter Cron, Tim Roloff, Reinhard Dummer, Mario Mandalà, Sandrine Bichet, Christel Genoud, Alexandra G Meyer, Manuele G Muraro, Giulio C Spagnoli, Daniela Taverna, Curzio Rüegg, Taha Merghoub, Daniela Massi, Huifang Tang, Mitchell P Levesque, Stephan Dirnhofer, Alfred Zippelius, Brian A Hemmings, Andreas Wicki
BRAF inhibitors (BRAFi) and the combination therapy of BRAF and MEK inhibitors (MEKi) were recently approved for therapy of metastatic melanomas harbouring the oncogenic BRAFV600 mutation. Although these therapies have shown pronounced therapeutic efficacy, the limited durability of the response indicates an acquired drug resistance that still remains mechanistically poorly understood at the molecular level. We conducted transcriptome gene profiling in BRAFi-treated melanoma cells and identified that Mer tyrosine kinase (MerTK) is specifically upregulated...
September 19, 2017: Oncotarget
https://www.readbyqxmd.com/read/29046513/history-and-practice-of-thyroid-fine-needle-aspiration-in-china-based-on-retrospective-study-of-the-practice-in-shandong-university-qilu-hospital
#10
Zhiyan Liu, Dongge Liu, Bowen Ma, Xiaofang Zhang, Peng Su, Li Chen, Qingdong Zeng
Cytology in China developed from nothing and underwent a long journey from gynecologic cytology to that of all organs, laying a solid foundation for new developments in the 21st century. Thyroid fine-needle aspiration (FNA) was primarily developed in an endocrinology department and then in the clinical laboratory department or pathology department in the 1970-80s. Wrights staining is popular in endocrine and clinical laboratory departments, while hematoxylin and eosin staining is common in pathology. Liquid based cytology is not common in thyroid FNA cytology, while BRAFV600E mutation analysis has been the most popular molecular test...
October 19, 2017: Journal of Pathology and Translational Medicine
https://www.readbyqxmd.com/read/29040023/dramatic-clinical-and-radiographic-response-to-braf-inhibition-in-a-patient-with-progressive-disseminated-optic-pathway-glioma-refractory-to-mek-inhibition
#11
Abhishek Bavle, Jeremy Jones, Frank Y Lin, Amy Malphrus, Adekunle Adesina, Jack Su
While clinical and radiographic responses to agents targeting the mitogen-activated protein kinases (MAPK) pathway have been repor-ted in pediatric low-grade gliomas (LGG), early phase trials indicate refractoriness to these medications in some of these patients. We report a patient with disseminated LGG with the BRAFV600E mutation, which was refractory to selumetinib, a MEK inhibitor, but subsequently showed immediate clinical and radiographic response to dabrafenib, a BRAF inhibitor, with sustained effect for 9 months prior to clinical progression...
October 17, 2017: Pediatric Hematology and Oncology
https://www.readbyqxmd.com/read/29035465/enhanced-specificity-of-braf-v600e-genotyping-using-wild-type-blocker-coupled-with-internal-competitive-reference-in-a-single-tube
#12
Jia Peng, Kun Wei, Shu Yu, Xiang Yang, Xiang Zhao, Yu Liu, Xiao-Yan Zhu, Na Zhao, Qing Huang, Wei-Ling Fu
BACKGROUND: Mutations in the BRAF gene have been strongly associated with failure in cancer treatment using epidermal growth factor receptor (EGFR) antibodies. To better diagnose and assess the prognosis of cancer patients, mutation screening of the BRAFV600E gene should be performed prior to clinical anti-tumor drug therapy to avoid ineffective treatment. METHODS: In our previous study, we developed a real-time wild-type blocking PCR (WTB-PCR), which can amplify the mutant allele at high efficiency while simultaneously inhibiting the amplification of wild-type alleles...
October 1, 2017: Clinical Laboratory
https://www.readbyqxmd.com/read/29033351/mouse-cutaneous-melanoma-induced-by-mutant-braf-arises-from-expansion-and-dedifferentiation-of-mature-pigmented-melanocytes
#13
Corinna Köhler, David Nittner, Florian Rambow, Enrico Radaelli, Fabio Stanchi, Niels Vandamme, Arianna Baggiolini, Lukas Sommer, Geert Berx, Joost J van den Oord, Holger Gerhardt, Cedric Blanpain, Jean-Christophe Marine
To identify the cells at the origin of melanoma, we combined single-cell lineage-tracing and transcriptomics approaches with time-lapse imaging. A mouse model that recapitulates key histopathological features of human melanomagenesis was created by inducing a BRafV600E-driven melanomagenic program in tail interfollicular melanocytes. Most targeted mature, melanin-producing melanocytes expanded clonally within the epidermis before losing their differentiated features through transcriptional reprogramming and eventually invading the dermis...
November 2, 2017: Cell Stem Cell
https://www.readbyqxmd.com/read/29025773/erdheim-chester-disease-atypical-presentation-of-a-rare-disease
#14
Cristian Ricardo Calandra, Ariel Bustos, Florencia Falcon, Naomi Arakaki
We report the clinical case of an adult patient referred to our hospital because of trismus due to a tumour in the right infratemporal and pterygomaxillary fossa. He referred hyporexia, weight loss and right trigeminal neuralgia. On physical examination, he had trismus and diplopia. On neuroimaging, the tumour invaded the central nervous system affecting the right temporal lobe and orbit, and the sellar region. Tumour biopsy revealed foamy histiocytes and isolated giant multinuclear cells immunoreactive to CD68 and negative to CD1a and S100...
October 11, 2017: BMJ Case Reports
https://www.readbyqxmd.com/read/28986383/copper-chelation-inhibits-brafv600e-driven-melanomagenesis-and-counters-resistance-to-brafv600e-and-mek1-2-inhibitors
#15
Donita C Brady, Matthew S Crowe, Danielle N Greenberg, Christopher M Counter
MEK1/2 and BRAFV600E inhibitors are used to treat BRAFV600E-positive melanoma, with other cancers under evaluation. Genetic perturbation of copper import or pharmacological reduction of copper with the clinical copper chelator TTM inhibits MEK1/2 kinase activity and reduces BRAFV600E-driven tumorigenesis. In this study, we report that TTM inhibited transformed growth of melanoma cell lines resistant to BRAF or MEK1/2 inhibitors and enhanced the antineoplastic activity of these inhibitors. TTM also provided a survival advantage in a genetically engineered mouse model of melanoma, and when accounting for putative overdosing, trended towards an increase in the survival benefit afforded by BRAF inhibition...
October 6, 2017: Cancer Research
https://www.readbyqxmd.com/read/28984141/dabrafenib-and-trametinib-in-brafv600e-mutated-glioma
#16
Nicholas F Brown, Thomas Carter, Neil Kitchen, Paul Mulholland
BRAFV600E mutations have been identified in a number of glioma subtypes, most frequently in pleomorphic xanthoastrocytoma, ganglioglioma, pilocytic astrocytoma, and epithelioid glioblastoma. Although the development of BRAF inhibitors has dramatically improved the clinical outcome for patients with BRAFV600E mutant tumors, resistance develops in a majority of patients due to reactivation of the MAPK pathway. Addition of MEK inhibition to BRAF inhibition improves survival. Here we report successful treatment of two patients with BRAFV600E mutant pleomorphic xanthoastrocytoma using the BRAF inhibitor dabrafenib in combination with the MEK inhibitor trametinib...
October 6, 2017: CNS Oncology
https://www.readbyqxmd.com/read/28975988/risk-factors-for-predicting-central-lymph-node-metastasis-in-papillary-thyroid-microcarcinoma-cn0-a-study-of-273-resections
#17
M Li, X-Y Zhu, J Lv, K Lu, M-P Shen, Z-L Xu, Z-S Wu
OBJECTIVE: The role of routine central lymph node dissection (CLND) for clinically central lymph node negative (CN0) papillary thyroid microcarcinoma (PTMC) remains uncertain. We aim to determine the predictive factors for central lymph node metastasis (CLNM) in papillary thyroid microcarcinoma. PATIENTS AND METHODS: A total of 273 patients diagnosed with clinically central lymph node negative PTMC from 2014 to 2016 were included. The predictive risk factors for CLNM were analyzed with respect to age, sex, tumor size, tumor multifocal, lymphadenectasis of lateral neck, capsular invasion, extra capsular spread (ECS), coexistence of chronic lymphocytic thyroiditis (Hashimoto thyroiditis, HT) and nodular goiter (NG), BRAFV600E mutation and subtype of papillary thyroid carcinoma (PTC)...
October 2017: European Review for Medical and Pharmacological Sciences
https://www.readbyqxmd.com/read/28961848/vemurafenib-in-patients-with-brafv600-mutation-positive-metastatic-melanoma-final-overall-survival-results-of-the-randomized-brim-3-study
#18
P B Chapman, C Robert, J Larkin, J B Haanen, A Ribas, D Hogg, O Hamid, P A Ascierto, A Testori, P C Lorigan, R Dummer, J A Sosman, K T Flaherty, I Chang, S Coleman, I Caro, A Hauschild, G A McArthur
Background: The BRIM-3 trial showed improved progression-free survival (PFS) and overall survival (OS) for vemurafenib compared with dacarbazine in treatment-naive patients with BRAFV600 mutation-positive metastatic melanoma. We present final OS data from BRIM-3. Patients and methods: Patients were randomly assigned in a 1 : 1 ratio to receive vemurafenib (960 mg twice daily) or dacarbazine (1000 mg/m2 every 3 weeks). OS and PFS were co-primary end points...
October 1, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/28947418/kit-suppresses-braf-v600e-mutant-melanoma-by-attenuating-oncogenic-ras-mapk-signaling
#19
James V Neiswender, Robert L Kortum, Caitlin Bourque, Melissa Kasheta, Leonard I Zon, Deborah K Morrison, Craig J Ceol
The receptor tyrosine kinase KIT promotes survival and migration of melanocytes during development, and excessive KIT activity hyperactivates the RAS/MAPK pathway and can drive formation of melanomas, most notably of rare melanomas that occur on volar and mucosal surfaces of the skin. The much larger fraction of melanomas that occur on sun-exposed skin is driven primarily by BRAF- or NRAS-activating mutations, but these melanomas exhibit a surprising loss of KIT expression, which raises the question of whether loss of KIT in these tumors facilitates tumorigenesis...
November 1, 2017: Cancer Research
https://www.readbyqxmd.com/read/28939558/targeting-the-mapk-signaling-pathway-in-cancer-promising-preclinical-activity-with-the-novel-selective-erk1-2-inhibitor-bvd-523-ulixertinib
#20
Ursula A Germann, Brinley F Furey, William Markland, Russell R Hoover, Alex M Aronov, Jeffrey J Roix, Micheal Hale, Diane M Boucher, David A Sorrell, Gabriel Martinez-Botella, Matthew Fitzgibbon, Paul Shapiro, Michael J Wick, Ramin Samadani, Kathryn Meshaw, Anna Groover, Gary DeCrescenzo, Mark Namchuk, Caroline M Emery, Saurabh Saha, Dean J Welsch
Aberrant activation of signaling through the RAS-RAF-MEK-ERK (MAPK) pathway is implicated in numerous cancers, making it an attractive therapeutic target. Although BRAF- and MEK-targeted combination therapy has demonstrated significant benefit beyond single-agent options, the majority of patients develop resistance and disease progression after approximately 12 months. Reactivation of ERK signaling is a common driver of resistance in this setting. Here we report the discovery of BVD-523 (ulixertinib), a novel, reversible, ATP-competitive ERK1/2 inhibitor with high potency and ERK1/2 selectivity...
September 22, 2017: Molecular Cancer Therapeutics
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