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https://www.readbyqxmd.com/read/27889782/molecular-pathology-a-requirement-for-precision-medicine-in-cancer
#1
Manfred Dietel
The increasing importance of targeting drugs and check-point inhibitors in the treatment of several tumor entities (breast, colon, lung, malignant melanoma, lymphoma, etc.) and the necessity of a companion diagnostic (HER2, (pan)RAS, EGFR, ALK, BRAF, ROS1, MET, PD-L1, etc.) is leading to new challenges for surgical pathology. Since almost all the biomarkers to be specifically detected are tissue based, a precise and reliable diagnostic is absolutely crucial. To meet this challenge surgical pathology has adapted a number of molecular methods (semi-quantitative immunohistochemistry, fluorescence in situ hybridization, PCR and its multiple variants, (pyro/Sanger) sequencing, next generation sequencing (amplicon, whole exome, whole genome), DNA arrays, methylation analyses, etc...
2016: Oncology Research and Treatment
https://www.readbyqxmd.com/read/27875628/clinical-genomic-profiling-identifies-tyk2-mutation-and-overexpression-in-patients-with-neurofibromatosis-type-1-associated-malignant-peripheral-nerve-sheath-tumors
#2
Angela C Hirbe, Madhurima Kaushal, Mukesh Kumar Sharma, Sonika Dahiya, Melike Pekmezci, Arie Perry, David H Gutmann
BACKGROUND: Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas that arise at an estimated frequency of 8% to 13% in individuals with neurofibromatosis type 1 (NF1). Compared with their sporadic counterparts, NF1-associated MPNSTs (NF1-MPNSTs) develop in young adults, frequently recur (approximately 50% of cases), and carry a dismal prognosis. As such, most individuals affected with NF1-MPNSTs die within 5 years of diagnosis, despite surgical resection combined with radiotherapy and chemotherapy...
November 22, 2016: Cancer
https://www.readbyqxmd.com/read/27864876/kinase-gene-fusions-in-defined-subsets-of-melanoma
#3
Jacqueline Turner, Kasey Couts, Jamie Sheren, Siriwimon Saichaemchan, Witthawat Ariyawutyakorn, Izabela Avolio, Ethan Cabral, Magdelena Glogowska, Carol Amato, Steven Robinson, Jennifer Hintzsche, Allison Applegate, Eric Seelenfreund, Rita Gonzalez, Keith Wells, Stacey Bagby, John Tentler, Aik-Choon Tan, Joshua Wisell, Marileila Varella-Garcia, William Robinson
Genomic rearrangements resulting in activating kinase fusions have been increasingly described in a number of cancers including malignant melanoma, but their frequency in specific melanoma subtypes has not been reported. We used break-apart fluorescence in-situ hybridization (FISH) to identify genomic rearrangements in tissues from 59 patients with various types of malignant melanoma including acral lentiginous, mucosal, superficial spreading, and nodular. We identified four genomic rearrangements involving the genes BRAF, RET, and ROS1...
November 19, 2016: Pigment Cell & Melanoma Research
https://www.readbyqxmd.com/read/27863911/crizotinib-for-ros1-patients-one-small-step-in-biomarker-testing-one-giant-leap-for-advanced-nsclc-patients
#4
EDITORIAL
Oscar Juan, Sanjay Popat
No abstract text is available yet for this article.
November 11, 2016: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
https://www.readbyqxmd.com/read/27844328/molecular-profiling-of-thymoma-and-thymic-carcinoma-genetic-differences-and-potential-novel-therapeutic-targets
#5
Franz Enkner, Bettina Pichlhöfer, Alexandru Teodor Zaharie, Milica Krunic, Tina Maria Holper, Stefan Janik, Bernhard Moser, Karin Schlangen, Barbara Neudert, Karin Walter, Brigitte Migschitz, Leonhard Müllauer
Thymoma and thymic carcinoma are thymic epithelial tumors (TETs). We performed a molecular profiling to investigate the pathogenesis of TETs and identify novel targets for therapy. We analyzed 37 thymomas (18 type A, 19 type B3) and 35 thymic carcinomas. The sequencing of 50 genes detected nonsynonymous mutations in 16 carcinomas affecting ALK, ATM, CDKN2A, ERBB4, FGFR3, KIT, NRAS and TP53. Only two B3 thymomas had a mutation in noncoding regions of the SMARCB1 and STK11 gene respectively. Three type A thymomas harbored a nonsynonymous HRAS mutation...
November 14, 2016: Pathology Oncology Research: POR
https://www.readbyqxmd.com/read/27836695/clinical-validation-of-a-next-generation-sequencing-genomic-oncology-panel-via-cross-platform-benchmarking-against-established-amplicon-sequencing-assays
#6
Sabah Kadri, Bradley C Long, Ibro Mujacic, Chao J Zhen, Michelle N Wurst, Shruti Sharma, Nadia McDonald, Nifang Niu, Sonia Benhamed, Jigyasa Tuteja, Tanguy Seiwert, Kevin White, Megan E McNerney, Carrie Fitzpatrick, Y Lynn Wang, Larissa V Furtado, Jeremy P Segal
Next-generation sequencing (NGS) genomic oncology profiling assays have emerged as key drivers of personalized cancer care and translational research. However, validation of these assays to meet strict clinical standards has been historically problematic because of both significant assay complexity and a scarcity of optimal validation samples. Herein, we present the clinical validation of 76 genes from a novel 1212-gene large-scale hybrid capture cancer sequencing assay (University of Chicago Medicine OncoPlus) using full-data comparisons against multiple clinical NGS amplicon-based assays to yield dramatic increases in per-sample data comparison efficiency compared with previously published validations...
November 8, 2016: Journal of Molecular Diagnostics: JMD
https://www.readbyqxmd.com/read/27833639/expression-of-concern-enhancement-of-rna-directed-dna-methylation-of-a-transgene-by-simultaneously-downregulating-a-ros1-ortholog-using-a-virus-vector-in-nicotiana-benthamiana
#7
COMMENT
https://www.readbyqxmd.com/read/27825731/molecular-testing-of-egfr-egfr-resistance-mutation-alk-and-ros1-achieved-by-ebus-tbna-in-chile
#8
Sebastián Fernandez-Bussy, Gonzalo Labarca, Yumay Pires, Iván Caviedes, Mauricio Burotto
No abstract text is available yet for this article.
November 5, 2016: Archivos de Bronconeumología
https://www.readbyqxmd.com/read/27825638/erlotinib-cabozantinib-or-erlotinib-plus-cabozantinib-as-second-line-or-third-line-treatment-of-patients-with-egfr-wild-type-advanced-non-small-cell-lung-cancer-ecog-acrin-1512-a-randomised-controlled-open-label-multicentre-phase-2-trial
#9
Joel W Neal, Suzanne E Dahlberg, Heather A Wakelee, Seena C Aisner, Michaela Bowden, Ying Huang, David P Carbone, Gregory J Gerstner, Rachel E Lerner, Jerome L Rubin, Taofeek K Owonikoko, Philip J Stella, Preston D Steen, Ahmed Ali Khalid, Suresh S Ramalingam
BACKGROUND: Erlotinib is approved for the treatment of all patients with advanced non-small-cell lung cancer (NSCLC), but is most active in the treatment of EGFR mutant NSCLC. Cabozantinib, a small molecule tyrosine kinase inhibitor, targets MET, VEGFR, RET, ROS1, and AXL, which are implicated in lung cancer tumorigenesis. We compared the efficacy of cabozantinib alone or in combination with erlotinib versus erlotinib alone in patients with EGFR wild-type NSCLC. METHODS: This three group, randomised, controlled, open-label, multicentre, phase 2 trial was done in 37 academic and community oncology practices in the USA...
November 4, 2016: Lancet Oncology
https://www.readbyqxmd.com/read/27822408/microarray-expression-profiling-identifies-genes-including-cytokines-and-biofunctions-as-diapedesis-associated-with-a-brain-metastasis-from-a-papillary-thyroid-carcinoma
#10
Hans-Juergen Schulten, Deema Hussein, Fatima Al-Adwani, Sajjad Karim, Jaudah Al-Maghrabi, Mona Al-Sharif, Awatif Jamal, Sherin Bakhashab, Jolanta Weaver, Fahad Al-Ghamdi, Saleh S Baeesa, Mohammed Bangash, Adeel Chaudhary, Mohammed Al-Qahtani
Brain metastatic papillary thyroid carcinomas (PTCs) are afflicted with unfavorable prognosis; however, the underlying molecular genetics of these rare metastases are virtually unknown. In this study, we compared whole transcript microarray expression profiles of a BRAF mutant, brain metastasis from a PTC, including its technical replicate (TR), with eight non-brain metastatic PTCs and eight primary brain tumors. The top 95 probe sets (false discovery rate (FDR) p-value < 0.05 and fold change (FC) > 2) that were differentially expressed between the brain metastatic PTC, including the TR, and both, non-brain metastatic PTCs and primary brain tumors were in the vast majority upregulated and comprise, e...
2016: American Journal of Cancer Research
https://www.readbyqxmd.com/read/27821131/frequency-of-egfr-t790m-mutation-and-multimutational-profiles-of-rebiopsy-samples-from-non-small-cell-lung-cancer-developing-acquired-resistance-to-egfr-tyrosine-kinase-inhibitors-in-japanese-patients
#11
Ryo Ko, Hirotsugu Kenmotsu, Masakuni Serizawa, Yasuhiro Koh, Kazushige Wakuda, Akira Ono, Tetsuhiko Taira, Tateaki Naito, Haruyasu Murakami, Mitsuhiro Isaka, Masahiro Endo, Takashi Nakajima, Yasuhisa Ohde, Nobuyuki Yamamoto, Kazuhisa Takahashi, Toshiaki Takahashi
BACKGROUND: The majority of non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutation eventually develop resistance to EGFR tyrosine kinase inhibitors (TKIs). Minimal information exists regarding genetic alterations in rebiopsy samples from Asian NSCLC patients who develop acquired resistance to EGFR-TKIs. METHODS: We retrospectively reviewed the medical records of patients with NSCLC harboring EGFR mutations who had undergone rebiopsies after developing acquired resistance to EGFR-TKIs...
November 8, 2016: BMC Cancer
https://www.readbyqxmd.com/read/27813706/global-genome-repair-factors-control-dna-methylation-patterns-in-arabidopsis
#12
Catherine Schalk, Jean Molinier
As obligate photosynthetic organisms plants are particularly exposed to the damaging effects of excess light and ultraviolet wavelengths, which can impact genome and epigenome dynamics by inducing DNA sequence and chromatin alterations. DNA DAMAGE-BINDING PROTEIN 2 (DDB2) is the main factor involved in the recognition of UV-induced DNA lesions during Global Genome Repair (GGR) in mammals and in plants. (1) In a recent study we reported that, in Arabidopsis, loss of DDB2 function alters DNA methylation patterns at many repeat loci and protein coding genes...
November 4, 2016: Plant Signaling & Behavior
https://www.readbyqxmd.com/read/27801963/nbp35-interacts-with-dre2-in-the-maturation-of-cytosolic-iron-sulfur-proteins-in-arabidopsis-thaliana
#13
Emma L Bastow, Katrine Bych, Jason C Crack, Nick E Le Brun, Janneke Balk
Proteins of the cytosolic pathway for iron-sulfur (FeS) cluster assembly are conserved, except that plants lack a gene for CFD1 (Cytosolic FeS cluster Deficient 1). This poses the question of how NBP35 (Nucleotide-Binding Protein 35 kDa), the heteromeric partner of CFD1 in metazoa, functions on its own in plants. Firstly, we created viable mutant alleles of NBP35 in Arabidopsis to overcome embryo lethality of previously reported knockout mutations. RNAi knockdown lines with less than 30% NBP35 protein surprisingly showed no developmental or biochemical differences to wild type...
November 1, 2016: Plant Journal: for Cell and Molecular Biology
https://www.readbyqxmd.com/read/27799065/a-case-study-of-an-integrative-genomic-and-experimental-therapeutic-approach-for-rare-tumors-identification-of-vulnerabilities-in-a-pediatric-poorly-differentiated-carcinoma
#14
Filemon S Dela Cruz, Daniel Diolaiti, Andrew T Turk, Allison R Rainey, Alberto Ambesi-Impiombato, Stuart J Andrews, Mahesh M Mansukhani, Peter L Nagy, Mariano J Alvarez, Andrea Califano, Farhad Forouhar, Beata Modzelewski, Chelsey M Mitchell, Darrell J Yamashiro, Lianna J Marks, Julia L Glade Bender, Andrew L Kung
BACKGROUND: Precision medicine approaches are ideally suited for rare tumors where comprehensive characterization may have diagnostic, prognostic, and therapeutic value. We describe the clinical case and molecular characterization of an adolescent with metastatic poorly differentiated carcinoma (PDC). Given the rarity and poor prognosis associated with PDC in children, we utilized genomic analysis and preclinical models to validate oncogenic drivers and identify molecular vulnerabilities...
October 31, 2016: Genome Medicine
https://www.readbyqxmd.com/read/27797842/crizotinib-in-ros1-rearranged-non-small-cell-lung-cancer-nsclc-from-response-to-resistance
#15
Eric Zhong, Hua Huang
We examined an immediate, but short-lived, response to crizotinib, a drug with a new indication for ROS1 rearranged non-small cell lung cancer (NSCLC) in a middle-aged non-smoker. The patient presented with metastatic NSCLC and extensive disease in multiple organs. He was treated with crizotinib 250 mg twice a day. Within 2-3 days, his condition rapidly improved, which was evident in a CT scan 2 months later. However, after 3 months of treatment, his condition deteriorated dramatically. The patient did not respond to ceritinib, a second-line drug that targets anaplastic lymphoma kinase, and died shortly after...
October 26, 2016: BMJ Case Reports
https://www.readbyqxmd.com/read/27797352/the-dna-demethylase-ros1-targets-genomic-regions-with-distinct-chromatin-modifications
#16
Kai Tang, Zhaobo Lang, Heng Zhang, Jian-Kang Zhu
The Arabidopsis ROS1/DEMETER family of 5-methylcytosine (5mC) DNA glycosylases are the first genetically characterized DNA demethylases in eukaryotes. However, the features of ROS1-targeted genomic loci are not well understood. In this study, we characterized ROS1 target loci in Arabidopsis Col-0 and C24 ecotypes. We found that ROS1 preferentially targets transposable elements (TEs) and intergenic regions. Compared with most TEs, ROS1-targeted TEs are closer to protein coding genes, suggesting that ROS1 may prevent DNA methylation spreading from TEs to nearby genes...
October 31, 2016: Nature Plants
https://www.readbyqxmd.com/read/27796337/phenotype-genotype-correlation-in-multiple-primary-lung-cancer-patients-in-china
#17
Yang Yang, Wei Yin, Wenxin He, Chao Jiang, Xiao Zhou, Xiao Song, Junjie Zhu, Ke Fei, Weijun Cao, Gening Jiang
Due to recent advances in high-resolution detection technology, multiple primary lung cancer (MPLC) is becoming an increasingly common diagnosis. However, the genotype-phenotype correlations in MPLC patients have not yet been assessed. In this study, we analyzed the clinical and pathological data for 129 consecutive MPLC patients who received curative surgery at the Tongji University Shanghai Pulmonary Hospital, China. We have screened 129 patients in the present study and found mutations in EGFR, BRAF, ROS1 and KRAS genes, as well as the rearrangement of the EML4-ALK gene in 113 patients...
October 31, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27794407/diagnostic-algorithm-for-detection-of-targetable-driver-mutations-in-lung-adenocarcinomas-comprehensive-analyses-of-205-cases-with-immunohistochemistry-real-time-pcr-and-fluorescence-in-situ-hybridization-methods
#18
Hua-Lin Kao, Yi-Chen Yeh, Chin-Hsuan Lin, Wei-Fang Hsu, Wen-Yu Hsieh, Hsiang-Ling Ho, Teh-Ying Chou
OBJECTIVES: Analysis of the targetable driver mutations is now recommended in all patients with advanced lung adenocarcinoma. Molecular-based methods are usually adopted, however, along with the implementation of highly sensitive and/or mutation-specific antibodies, immunohistochemistry (IHC) has been considered an alternative method for identifying driver mutations in lung adenocarcinomas. MATERIALS AND METHODS: A total of 205 lung adenocarcinomas were examined for EGFR mutations and ALK and ROS1 rearrangements using real-time PCR, fluorescence in situ hybridization (FISH) and IHC in parallel...
November 2016: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
https://www.readbyqxmd.com/read/27780853/the-potent-alk-inhibitor-brigatinib-ap26113-overcomes-mechanisms-of-resistance-to-first-and-second-generation-alk-inhibitors-in-preclinical-models
#19
Sen Zhang, Rana Anjum, Rachel Squillace, Sara Nadworny, Tianjun Zhou, Jeff Keats, Yaoyu Ning, Scott D Wardwell, David Miller, Youngchul Song, Lindsey Eichinger, Lauren Moran, Wei-Sheng Huang, Shuangying Liu, Dong Zou, Yihan Wang, Qurish Mohemmad, Hyun Gyung Jang, Emily Ye, Narayana Narasimhan, Frank Wang, Juan Miret, Xiaotian Zhu, Tim Clackson, David Dalgarno, William C Shakespeare, Victor M Rivera
PURPOSE: Non-small cell lung cancers (NSCLCs) harboring ALK gene rearrangements (ALK(+)) typically become resistant to the first-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) crizotinib through development of secondary resistance mutations in ALK or disease progression in the brain. Mutations that confer resistance to second-generation ALK TKIs ceritinib and alectinib have also been identified. Here, we report the structure and first comprehensive preclinical evaluation of the next-generation ALK TKI brigatinib...
October 25, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27770508/nrg1-fusion-in-a-french-cohort-of-invasive-mucinous-lung-adenocarcinoma
#20
Michaël Duruisseaux, Anne McLeer-Florin, Martine Antoine, Sanaz Alavizadeh, Virginie Poulot, Roger Lacave, Nathalie Rabbe, Jacques Cadranel, Marie Wislez
Invasive mucinous lung adenocarcinoma (IMA) is a rare subtype of lung adenocarcinoma with no effective treatment option in advanced disease. KRAS mutations occur in 28-87% of the cases. NRG1 fusions were recently discovered in KRAS-negative IMA cases and otherwise negative for known driver oncogenes and could represent an attractive therapeutic target. Published data suggest that NRG1 fusions occur essentially in nonsmoking Asian women. From an IMA cohort of 25 French patients of known ethnicity, driver oncogenes EGFR, KRAS, BRAF, ERBB2 mutations, and ALK and ROS1 rearrangements presence were analyzed...
October 21, 2016: Cancer Medicine
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