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https://www.readbyqxmd.com/read/29349042/an-optimized-targeted-next-generation-sequencing-approach-for-sensitive-detection-of-single-nucleotide-variants
#1
S Stasik, C Schuster, C Ortlepp, U Platzbecker, M Bornhäuser, J Schetelig, G Ehninger, G Folprecht, C Thiede
Monitoring of minimal residual disease (MRD) has become an important clinical aspect for early relapse detection during follow-up care after cancer treatment. Still, the sensitive detection of single base pair point mutations via Next-Generation Sequencing (NGS) is hampered mainly due to high substitution error rates. We evaluated the use of NGS for the detection of low-level variants on an Ion Torrent PGM system. As a model case we used the c.1849G > T (p.Val617Phe) mutation of the JAK2-gene. Several reaction parameters (e...
May 2018: Biomolecular Detection and Quantification
https://www.readbyqxmd.com/read/29343524/antitumor-properties-of-raf709-a-highly-selective-and-potent-inhibitor-of-raf-kinase-dimers-in-tumors-driven-by-mutant-ras-or-braf
#2
Wenlin Shao, Yuji Mishina, Yun Feng, Giordano Caponigro, Vesselina G Cooke, Stacy Rivera, Yingyun Wang, Fang Shen, Joshua M Korn, Lesley Mathews Griner, Gisele Nishiguchi, Alice Rico, John Tellew, Jacob Haling, Robert Aversa, Valery R Polyakov, Richard Zang, Mohammad Hekmat-Nejad, Payman Amiri, Mallika Singh, Nicholas Keen, Michael P Dillon, Emma Lees, Savithri Ramurthy, William R Sellers, Darrin D Stuart
Resistance to the RAF inhibitor vemurafenib arises commonly in melanomas driven by the activated BRAF oncogene. Here we report antitumor properties of RAF709, a novel ATP-competitive kinase inhibitor with high potency and selectivity against RAF kinases. RAF709 exhibited a mode of RAF inhibition distinct from RAF monomer inhibitors such as vemurafenib, showing equal activity against both RAF monomers and dimers. As a result, RAF709 inhibited MAPK signaling activity in tumor models harboring either BRAFV600 alterations or mutant N- and KRAS-driven signaling, with minimal paradoxical activation of wild-type RAF...
January 17, 2018: Cancer Research
https://www.readbyqxmd.com/read/29338978/non-risk-adapted-surveillance-for-stage-i-testicular-cancer-critical-review-and-summary
#3
REVIEW
Phillip Martin Pierorazio, Peter Albers, Peter C Black, Torgrim Tandstad, Axel Heidenreich, Nicola Nicolai, Craig Nichols
CONTEXT: Cancer-specific survival for men with clinical stage I testicular cancer (CSITC) is uniformly excellent. Non-risk-adapted active surveillance (NRAS) is a management strategy for CSITC to minimize overtreatment and avoid possible long-term side effects of adjuvant therapy. OBJECTIVE: To review the evidence regarding oncologic outcomes for men with CSITC undergoing NRAS and discuss ongoing controversies in the management of CSITC. EVIDENCE ACQUISITION: MEDLINE/PubMed, Embase, and the Cochrane Central Register of Controlled Trials were searched from January 1, 1987 through January 1, 2017...
January 12, 2018: European Urology
https://www.readbyqxmd.com/read/29335867/can-ct-based-radiomics-signature-predict-kras-nras-braf-mutations-in-colorectal-cancer
#4
Lei Yang, Di Dong, Mengjie Fang, Yongbei Zhu, Yali Zang, Zhenyu Liu, Hongmei Zhang, Jianming Ying, Xinming Zhao, Jie Tian
OBJECTIVES: To investigate whether CT-based radiomics signature can predict KRAS/NRAS/BRAF mutations in colorectal cancer (CRC). METHODS: This retrospective study consisted of a primary cohort (n = 61) and a validation cohort (n = 56) with pathologically confirmed CRC. Patients underwent KRAS/NRAS/BRAF mutation tests and contrast-enhanced CT before treatment. A total of 346 radiomics features were extracted from portal venous-phase CT images of the entire primary tumour...
January 15, 2018: European Radiology
https://www.readbyqxmd.com/read/29333594/ras-testing-for-colorectal-cancer-patients-is-reliable-in-european-laboratories-that-pass-external-quality-assessment
#5
V Tack, M J L Ligtenberg, A G Siebers, P D M Rombout, P D Dabir, R D A Weren, J H J M van Krieken, E M C Dequeker
Wild-type status of KRAS and the NRAS gene (exon 2, 3, and 4) in the tumor should be determined before treatment of metastatic colorectal cancer (mCRC) patients with EGFR-targeting agents. There is a large variation in test methods to determine RAS status, and more sensitive detection methods were recently introduced. Data from quality assessment programs indicate substantial error rates. This study assessed the completeness and correctness of RAS testing in European laboratories that successfully passed external quality assessment (EQA)...
January 15, 2018: Virchows Archiv: An International Journal of Pathology
https://www.readbyqxmd.com/read/29332123/braf-nras-and-gnaq-mutations-in-conjunctival-melanocytic-nevi
#6
Jasmine H Francis, Hans E Grossniklaus, Larissa A Habib, Brian Marr, David H Abramson, Klaus J Busam
Purpose: To evaluate BRAF, NRAS, and GNAQ mutations in surgical specimens of common and blue conjunctival melanocytic nevi. Methods: Surgical specimens from 25 conjunctival melanocytic nevi (23 common and 2 blue) of 25 patients were evaluated. All common nevi were analyzed immunohistochemically for the expression of BRAF V600E or NRAS Q61R. One lesion with negative immunoreactivity and for all blue nevi, a hybridization capture-based next-generation sequencing method was employed for mutation analysis...
January 1, 2018: Investigative Ophthalmology & Visual Science
https://www.readbyqxmd.com/read/29329780/oncogenic-rac1-and-nras-drive-resistance-to-endoplasmic-reticulum-stress-through-mek-erk-signalling
#7
Michael D Bright, Paul A Clarke, Paul Workman, Faith E Davies
Cancer cells are able to survive under conditions that cause endoplasmic reticulum stress (ER-stress), and can adapt to this stress by upregulating cell-survival signalling pathways and down-regulating apoptotic pathways. The cellular response to ER-stress is controlled by the unfolded protein response (UPR). Small Rho family GTPases are linked to many cell responses including cell growth and apoptosis. In this study, we investigate the function of small GTPases in cell survival under ER-stress. Using siRNA screening we identify that RAC1 promotes cell survival under ER-stress in cells with an oncogenic N92I RAC1 mutation...
January 9, 2018: Cellular Signalling
https://www.readbyqxmd.com/read/29327707/appendiceal-goblet-cell-carcinoids-and-adenocarcinomas-ex-goblet-cell-carcinoid-are-genetically-distinct-from-primary-colorectal-type-adenocarcinoma-of-the-appendix
#8
Moritz Jesinghaus, Björn Konukiewitz, Sebastian Foersch, Albrecht Stenzinger, Katja Steiger, Alexander Muckenhuber, Claudia Groß, Martin Mollenhauer, Wilfried Roth, Sönke Detlefsen, Wilko Weichert, Günter Klöppel, Nicole Pfarr, Anna Melissa Schlitter
The appendix gives rise to goblet cell carcinoids, which represent special carcinomas with distinct biological and histological features. Their genetic background and molecular relationship to colorectal adenocarcinoma is largely unknown. We therefore performed a next-generation sequencing analysis of 25 appendiceal carcinomas including 11 goblet cell carcinoids, 7 adenocarcinomas ex-goblet cell carcinoid, and 7 primary colorectal-type adenocarcinomas, using a modified Colorectal Cancer specific Panel comprising 32 genes linked to colorectal and neuroendocrine tumorigenesis...
January 12, 2018: Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc
https://www.readbyqxmd.com/read/29317515/intratumoural-heterogeneity-may-hinder-precision-medicine-strategies-in-patients-with-clear-cell-renal-cell-carcinoma
#9
Maria Rosaria Raspollini, Ilaria Montagnani, Rodolfo Montironi, Francesca Castiglione, Guido Martignoni, Liang Cheng, Antonio Lopez-Beltran
Clear cell renal cell carcinoma (ccRCC) is an heterogeneous tumour at architectural, cellular and molecular level, a reason why the 2014 International Society of Urological Pathology consensus recommended wide sampling of RCC masses to include at least 1 block/cm of tumour together with perpendicular sections of the tumour/perinephric fat interface and the tumour/renal sinus interface. Intratumoural molecular heterogeneity may be a limitation at the moment of defining precision medicine strategies based on gene mutation status...
January 9, 2018: Journal of Clinical Pathology
https://www.readbyqxmd.com/read/29316280/giant-congenital-melanocytic-nevus-with-vascular-malformation-and-epidermal-cysts-associated-with-a-somatic-activating-mutation-in-braf
#10
Heather C Etchevers, Christian Rose, Birgit Kahle, Helmuth Vorbringer, Frédéric Fina, Pauline Heux, Irina Berger, Benjamin Schwarz, Stéphane Zaffran, Nicolas Macagno, Sven Krengel
Giant congenital melanocytic nevi may be symptomatically isolated, or syndromic. Associations with capillary malformations are exceptional, and development of epidermal cysts has not been described. A 71-year old patient with a giant congenital melanocytic nevus of the lower back, buttocks and thighs was asymptomatic except for unexpected hemorrhage during partial surgical excision years before. Blunt trauma at age 64 initiated recurrent, severe pain under the nevus; multiple large epidermal cysts then developed within it...
January 5, 2018: Pigment Cell & Melanoma Research
https://www.readbyqxmd.com/read/29313669/design-of-small-molecules-that-compete-with-nucleotide-binding-to-an-engineered-oncogenic-kras-allele
#11
Yan Zhang, Mare-Helene Larraufie, Leila Musavi, Hemanth Akkiraju, Lewis M Brown, Brent R Stockwell
RAS mutations are found in 30% of all human cancers, with KRAS the most frequently mutated among the three RAS isoforms (KRAS, NRAS, HRAS). However, directly targeting oncogenic KRAS with small molecules in the nucleotide-binding site has been difficult due to the high affinity of KRAS for GDP and GTP. We designed an engineered allele of KRAS, and a covalent inhibitor that competes for GTP and GDP. This ligand-receptor combination demonstrates that the high affinity of GTP/GDP for RAS proteins can be overcome with a covalent inhibitor and a suitably engineered binding site...
January 9, 2018: Biochemistry
https://www.readbyqxmd.com/read/29307989/gene-mutations-in-stool-from-gastric-and-colorectal-neoplasia-patients-by-next-generation-sequencing
#12
Omar Youssef, Virinder Sarhadi, Homa Ehsan, Tom Böhling, Monika Carpelan-Holmström, Selja Koskensalo, Pauli Puolakkainen, Arto Kokkola, Sakari Knuutila
AIM: To study cancer hotspot mutations by next-generation sequencing (NGS) in stool DNA from patients with different gastrointestinal tract (GIT) neoplasms. METHODS: Stool samples were collected from 87 Finnish patients diagnosed with various gastric and colorectal neoplasms, including benign tumors, and from 14 healthy controls. DNA was isolated from stools by using the PSP® Spin Stool DNA Plus Kit. For each sample, 20 ng of DNA was used to construct sequencing libraries using the Ion AmpliSeq Cancer Hotspot Panel v2 or Ion AmpliSeq Colon and Lung Cancer panel v2...
December 21, 2017: World Journal of Gastroenterology: WJG
https://www.readbyqxmd.com/read/29307569/is-nanoclustering-essential-for-all-oncogenic-kras-pathways-can-it-explain-why-wild-type-kras-can-inhibit-its-oncogenic-variant
#13
REVIEW
Ruth Nussinov, Chung-Jung Tsai, Hyunbum Jang
Membrane-anchored oncogenic KRas can dimerize, form nanoclusters, and signal through the MAPK (Raf/MEK/ERK) and PI3Kα/Akt/mTOR. Both pathways are needed in KRAS-driven proliferation. Here we ask: Is oncogenic KRas nanoclustering (or dimerization) essential for all KRas signaling pathways? Raf kinase domain dimerization, thus MAPK activation, requires KRas nanoclusters. By contrast, the PI3Kα heterodimer acts as a monomeric unit; thus, does PI3Kα activation and PI3Kα/Akt/mTOR signaling require nanoclustering? Further, calmodulin binds only to oncogenic KRas4B...
January 5, 2018: Seminars in Cancer Biology
https://www.readbyqxmd.com/read/29305225/droplet-digital-pcr-for-mutation-detection-in-formalin-fixed-paraffin-embedded-melanoma-tissues-a-comparison-with-sanger-sequencing-and-pyrosequencing
#14
Ashleigh C McEvoy, Benjamin A Wood, Nima M Ardakani, Michelle Pereira, Robert Pearce, Lester Cowell, Cleo Robinson, Fabienne Grieu-Iacopetta, Alexander J Spicer, Benhur Amanuel, Melanie Ziman, Elin S Gray
Identification of somatic mutations is crucial to guide therapeutic decisions for personalized melanoma treatment. However, genetic analysis of the tumor is usually performed on limited and often low-quality DNA, from tumors with low tumor cellularity and high tumor heterogeneity. Different mutation detection platforms exist with varying analytical sensitivities. Here we evaluated the detection of common mutations in BRAF, NRAS, and TERT-promoter in 40 melanoma formalin-fixed, paraffin-embedded tissues using droplet digital PCR (ddPCR), and compared the results to the detection rate obtained by Sanger sequencing and pyrosequencing...
January 2, 2018: Journal of Molecular Diagnostics: JMD
https://www.readbyqxmd.com/read/29298843/nis-expression-in-thyroid-tumors-relation-with-prognosis-clinicopathological-and-molecular-features
#15
Catarina Tavares, Maria João Coelho, Catarina Eloy, Miguel Melo, Adriana Gaspar da Rocha, Ana Pestana, Rui Batista, Luciana Bueno Ferreira, Elisabete Rios, Samia Selmi-Ruby, Bruno Cavadas, Luísa Pereira, Manuel Sobrinho Simões, Paula Soares
Thyroid cancer therapy is based on surgery followed by radioiodine treatment. The incorporation of radioiodine by cancer cells is mediated by sodium iodide symporter (NIS) (codified by the SLC5A5 gene), that is functional only when targeted to the cell membrane. We aimed to evaluate if NIS expression in thyroid primary tumors would be helpful in predicting tumor behavior, response to therapy and prognosis. NIS expression was addressed by qPCR and immunohistochemistry. In order to validate our data, we also studied SLC5A5 expression on 378 primary papillary thyroid carcinomas from The Cancer Genome Atlas (TCGA) database...
January 2018: Endocrine Connections
https://www.readbyqxmd.com/read/29295643/the-genomic-landscape-of-two-burkitt-lymphoma-cases-and-derived-cell-lines-comparison-between-primary-and-relapse-samples
#16
Claudia M Wever, Dominique Geoffrion, Bruno M Grande, Stephen Yu, Miguel Alcaide, Maryse Lemaire, Yasser Riazalhosseini, Josée Hébert, Christina Gavino, Donald C Vinh, Tina Petrogiannis-Haliotis, Svetlana Dmitrienko, Koren K Mann, Ryan D Morin, Nathalie A Johnson
Relapse occurs in 10-40% of Burkitt lymphoma (BL) patients that have completed intensive chemotherapy regimens and is typically fatal. While treatment-naive BL has been characterized, the genomic landscape of BL at the time of relapse (rBL) has never been reported. Here, we present a genomic characterization of two rBL patients. The diagnostic samples had mutations common in BL, including MYC and CCND3. Additional mutations were detected at relapse, affecting important pathways such as NFκB (IKBKB) and MEK/ERK (NRAS) signaling, glutamine metabolism (SIRT4), and RNA processing (ZFP36L2)...
January 3, 2018: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/29290764/aminoacylase-3-is-a-new-potential-marker-and-therapeutic-target-in-hepatocellular-carcinoma
#17
Kirill Tsirulnikov, Sergio Duarte, Anamika Ray, Nakul Datta, Ali Zarrinpar, Lin Hwang, Kym Faull, Alexander Pushkin, Ira Kurtz
Ras proteins (HRas, KRas and NRas) are common oncogenes that require membrane association for activation. Previous approaches to block/inhibit Ras membrane association were unsuccessful for cancer treatment in human clinical studies. In the present study we utilized a new approach to decrease Ras membrane association in hepatocellular carcinoma (HCC) cell lines via inhibition of an enzyme aminoacylase 3 (AA3; EC 3.5.1.114). AA3 expression was significantly elevated in the livers of HCC patients and HCC cell lines...
2018: Journal of Cancer
https://www.readbyqxmd.com/read/29285234/targeted-next-generation-sequencing-in-chinese-colorectal-cancer-patients-guided-anti-egfr-treatment-and-facilitated-precision-cancer-medicine
#18
Helei Hou, Dong Liu, Chuantao Zhang, Yanxia Jiang, Guifang Lu, Na Zhou, Xiaonan Yang, Xiaoping Zhang, Zhuokun Li, Hongmei Zhu, Zhaoyang Qian, Xiaochun Zhang
Objective: Colorectal cancer (CRC) patients with both RAS and BRAF wild-type tumors determined by non-next generation sequencing (NGS) testing may still not respond due to the presence of additional mutated genes such as PIK3CA or PTEN. In this study, a broad, hybrid capture-based NGS assay was used to identify RAS, BRAF and additional targetable genetic alterations from Chinese CRC tissues. Methods: Fifty-seven cases of CRC were enrolled, and all the patients signed the informed consent...
December 1, 2017: Oncotarget
https://www.readbyqxmd.com/read/29279013/novel-approaches-to-diagnosis-and-treatment-of-juvenile-myelomonocytic-leukemia
#19
Franco Locatelli, Mattia Algeri, Pietro Merli, Luisa Strocchio
Juvenile myelomonocytic leukemia (JMML) is a clonal hematopoietic disorder of infancy/early childhood, resulting from oncogenic mutations in genes involved in the Ras pathway. As JMML often exhibits an aggressive course, the timing of diagnosis and treatment is critical to outcome. Areas covered: This review summarizes current approaches to diagnosis and treatment of JMML, highlighting most recent insights into genetic and epigenetic mechanisms underlying the disease, and providing an overview of novel potential therapeutic strategies...
January 3, 2018: Expert Review of Hematology
https://www.readbyqxmd.com/read/29278520/malignant-struma-ovarii-harboring-a-unique-nras-mutation-case-report-and-review-of-the-literature
#20
Carlo Gobitti, Alessandro Sindoni, Chiara Bampo, Tanja Baresic, Giorgio Giorda, Lara Alessandrini, Vincenzo Canzonieri, Giovanni Franchin, Eugenio Borsatti
Struma ovarii (SO), a rare tumor containing at least 50% of thyroid tissue, represents approximately 5% of all ovarian teratomas; its malignant transformation rate is reported to occur in up to 10% of cases and metastases occur in about 5-6% of them. We describe a 36-year old woman who underwent laparoscopic left annessectomy two years earlier because of an ovarian cyst. Follow-up imaging revealed a right adnexal mass, ascitis and peritoneal nodes that were diagnosed as comprising a malignant SO with peritoneal secondary localizations at histopathology performed after intervention...
July 2017: Hormones: International Journal of Endocrinology and Metabolism
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