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https://www.readbyqxmd.com/read/29052598/association-between-clinicopathological-characteristics-and-ras-mutation-in-colorectal-cancer
#1
Johan Rimbert, Gaëlle Tachon, Audelaure Junca, Claire Villalva, Lucie Karayan-Tapon, David Tougeron
In colorectal cancer, KRAS (exons 2, 3, and 4) and NRAS (exons 2, 3, and 4) mutations are associated with resistance to antiepidermal growth factor receptor monoclonal antibodies, and BRAF mutation is a molecular marker of poor prognosis. KRAS exon 2 and BRAF-mutated colorectal cancers have well-known distinct clinicopathological characteristics. Comparison of tumors with different RAS status (exons 2, 3, and 4 of KRAS and NRAS) based on their clinicopathological characteristics has never been established. All colorectal cancer patients with RAS and BRAF testing from 2011 to 2015 were included in this observational retrospective study...
October 20, 2017: Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc
https://www.readbyqxmd.com/read/29051323/epithelial-to-mesenchymal-transition-antagonizes-response-to-targeted-therapies-in-lung-cancer-by-suppressing-bim
#2
Kyung-A Song, Matthew J Niederst, Timothy L Lochmann, Aaron N Hata, Hidenori Kitai, Jungoh Ham, Konstantinos V Floros, Mark A Hicks, Haichuan Hu, Hillary E Mulvey, Yotam Drier, Daniel A R Heisey, Mark T Hughes, Neha U Patel, Elizabeth Lockerman, Angel R Garcia, Shawn Gillepsie, Hannah L Archibald, Maria Gomez-Caraballo, Tara J Nulton, Brad Windle, Zofia Piotrowska, Sinem E Sahingur, Shirley M Taylor, Mikhail G Dozmorov, Lecia V Sequist, Bradley E Bernstein, Hiromichi Ebi, Jeffrey A Engelman, Anthony C Faber
PURPOSE: Epithelial-to-mesenchymal transition (EMT) confers resistance to a number of targeted therapies and chemotherapies. However, it has been unclear why EMT promotes resistance, thereby impairing progress to overcome it. EXPERIMENTAL DESIGN: We have developed several models of EMT-mediated resistance to EGFR inhibitors (EGFRi) in EGFR mutant lung cancers to evaluate a novel mechanism of EMT-mediated resistance. Results: We observed that mesenchymal EGFR mutant lung cancers are resistant to EGFRi-induced apoptosis via insufficient expression of BIM, preventing cell death despite potent suppression of oncogenic signaling following EGFRi treatment...
October 19, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29051321/liquid-biopsies-using-plasma-exosomal-nucleic-acids-and-plasma-cell-free-dna-compared-with-clinical-outcomes-of-patients-with-advanced-cancers
#3
Lino Möhrmann, Helen Huang, David S Hong, Apostolia M Tsimberidou, Siqing Fu, Sarina Piha-Paul, Vivek Subbiah, Daniel D Karp, Aung Naing, Anne K Krug, Daniel Enderle, Tina Priewasser, Mikkel Noerholm, Erez Eitan, Christine Coticchia, Georg Stoll, Lisa-Marie Jordan, Cathy Eng, Scott Kopetz, Johan Skog, Funda Meric-Bernstam, Filip Janku
PURPOSE: Blood-based liquid biopsies offer easy access to genomic material for molecular diagnostics in cancer. Commonly used cell-free DNA (cfDNA) originates from dying cells. Exosomal nucleic acids (exoNA) originate from living cells, which can better reflect underlying cancer biology. EXPERIMENTAL DESIGN: Next-generation sequencing (NGS) was used to test exosomal nucleic acids (exoNA), and droplet digital PCR (ddPCR) and BEAMing PCR were used to test cfDNA for BRAF V600, KRAS G12/G13, and EGFR exon19del/L858R mutations in 43 patients with progressing advanced cancers...
October 19, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29051265/regulation-of-notch-signaling-by-rab7-and-rab8-requires-carboxyl-methylation-by-icmt
#4
Helen Court, Ian M Ahearn, Marc Amoyel, Erika A Bach, Mark R Philips
Isoprenylcysteine carboxyl methyltransferase (ICMT) methylesterifies C-terminal prenylcysteine residues of CaaX proteins and some RAB GTPases. Deficiency of either ICMT or NOTCH1 accelerates pancreatic neoplasia in Pdx1-Cre;LSL-Kras(G12D) mice, suggesting that ICMT is required for NOTCH signaling. We used Drosophila melanogaster wing vein and scutellar bristle development to screen Rab proteins predicted to be substrates for ICMT (ste14 in flies). We identified Rab7 and Rab8 as ICMT substrates that when silenced phenocopy ste14 deficiency...
October 19, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/29050937/integrated-expression-profiling-of-potassium-channels-identifys-kcnn4-as-a-prognostic-biomarker-of-pancreatic-cancer
#5
Shuheng Jiang, Lili Zhu, Jianyu Yang, Lipeng Hu, Jianren Gu, Xin Xing, Yongwei Sun, Zhigang Zhang
Dysregulated potassium (K(+)) channels have previously been shown to promote the development and progression of many types of cancers. Meanwhile, K(+) channels are particularly important in regulating the endocrine and exocrine functions of pancreas. However, the expression pattern and prognostic significance of K(+) channels in pancreatic ductal adenocarcinoma (PDAC) remain unknown. In this study, by screening a GEO dataset containing 36 microdissected PDAC and matching normal pancreatic tissue samples, four differentially expressed K(+) channels (KCNJ5, KCNJ16, KCNN4 and KCNK1) were identified in PDAC...
October 16, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29050231/a-phase-i-study-of-foretinib-plus-erlotinib-in-patients-with-previously-treated-advanced-non-small-cell-lung-cancer-canadian-cancer-trials-group-ind-196
#6
Natasha B Leighl, Ming-Sound Tsao, Geoffrey Liu, Dongsheng Tu, Cheryl Ho, Frances A Shepherd, Nevin Murray, John R Goffin, Garth Nicholas, Shingo Sakashita, Zhuo Chen, Lucia Kim, Jean Powers, Lesley Seymour, Glenwood Goss, Penelope A Bradbury
PURPOSE: MET and AXL mediate resistance to EGFR TKI in NSCLC. Foretinib, a MET/RON/AXL/TIE-2/VEGFR kinase inhibitor may overcome EGFR kinase resistance. This dose escalation study combined foretinib and erlotinib in advanced pretreated NSCLC patients. EXPERIMENTAL DESIGN: The primary endpoint was to define the RP2D of foretinib plus erlotinib as continuous oral daily dosing. Secondary objectives included safety, pharmacokinetics, response and potential biomarkers of response including EGFR, KRAS genotype, MET, AXL expression, and circulating HGF levels...
September 19, 2017: Oncotarget
https://www.readbyqxmd.com/read/29050228/mutation-landscape-and-intra-tumor-heterogeneity-of-two-manecs-of-the-esophagus-revealed-by-multi-region-sequencing
#7
Wenqing Yuan, Zhen Liu, Wanjun Lei, Li Sun, Haijun Yang, Yu Wang, Shweta Ramdas, Xiao Dong, Ruiping Xu, Hong Cai, Jun Z Li, Yang Ke
Mixed adenoneuroendocrine carcinoma (MANEC) in the esophagus is an infrequent but highly malignant cancer with few known genomic alterations. We conducted whole-exome sequencing and whole-genome SNP genotyping for 4-6 tumor subregions and 5-6 adjacent normal tissue sites and 1-3 lymph node metastases in two esophageal MANECs to detect somatic mutations and copy number alterations, and to explore their spatial heterogeneity and underlying clonal structure. TP53 mutation, RB1 deletion or LOH, and PIK3CA, PTEN, KRAS, SOX2, DVL3, TP63 amplification appeared in all regions in both tumors...
September 19, 2017: Oncotarget
https://www.readbyqxmd.com/read/29048669/microrna%C3%A2-337-inhibits-colorectal-cancer-progression-by-directly-targeting-kras-and-suppressing-the-akt-and-erk-pathways
#8
Xuerong Liu, Yan Wang, Jinglong Zhao
Colorectal cancer (CRC) is the third most common cancer and the fourth most common cause of cancer-related death worldwide. Tumour progression and development in CRC is a multi-step process involving a large number of genetic and epigenetic alterations. Previous studies indicated that abnormally expressed microRNAs play critical roles in CRC through regulation of oncogenic and tumour-suppressor genes. Hence, determination of the function of microRNAs may provide novel therapeutic targets for CRC diagnosis and treatments...
September 25, 2017: Oncology Reports
https://www.readbyqxmd.com/read/29048575/microrna-binding-site-polymorphisms-in-genes-involved-in-colorectal-cancer-etiopathogenesis-and-their-impact-on-disease-prognosis
#9
Michaela Schneiderova, Alessio Naccarati, Barbara Pardini, Fabio Rosa, Cornelia Di Gaetano, Katerina Jiraskova, Alena Opattova, Miroslav Levy, Karel Veskrna, Veronika Veskrnova, Tomas Buchler, Stefano Landi, Pavel Vodicka, Veronika Vymetalkova
According to the Vogelstein's model of colorectal carcinogenesis, genetic variations in highly penetrant genes may be involved in the colorectal cancer (CRC) pathogenesis. Similarly, aberrant function and/or altered expression of microRNAs (miRNAs) often occur in CRC. In this context, polymorphisms in miRNA-binding sites (miRSNPs) may affect miRNA/target gene interaction, resulting in differential mRNA/protein expression and increased susceptibility to common diseases. To explore this phenomenon, we have mined the 3' untranslated regions (3'UTRs) of genes known to be frequently mutated in CRC to search for miRSNPs and tested their association with CRC risk and clinical outcome...
October 17, 2017: Mutagenesis
https://www.readbyqxmd.com/read/29048416/increased-frequency-of-kras-mutations-in-african-americans-compared-with-caucasians-in-sporadic-colorectal-cancer
#10
Jonas J Staudacher, Cemal Yazici, Vadim Bul, Joseph Zeidan, Ahmer Khalid, Yinglin Xia, Nancy Krett, Barbara Jung
OBJECTIVES: The basis for over-representation of colorectal cancer (CRC) in African-American (AA) populations compared with Caucasians are multifactorial and complex. Understanding the mechanisms for this racial disparity is critical for delivery of better care. Several studies have investigated sporadic CRC for differences in somatic mutations between AAs and Caucasians, but owing to small study sizes and conflicting results to date, no definitive conclusions have been reached. METHODS: Here, we present the first systematic literature review and meta-analysis investigating the mutational differences in sporadic CRC between AAs and Caucasians focused on frequent driver mutations (APC,TP53, KRAS,PI3CA, FBXW7,SMAD4, and BRAF)...
October 19, 2017: Clinical and Translational Gastroenterology
https://www.readbyqxmd.com/read/29047229/enhanced-inflammation-and-attenuated-tumor-suppressor-pathways-are-associated-with-oncogene-induced-lung-tumors-in-aged-mice
#11
Neha Parikh, Ryan L Shuck, Mihai Gagea, Lanlan Shen, Lawrence A Donehower
Aging is often accompanied by a dramatic increase in cancer susceptibility. To gain insights into how aging affects tumor susceptibility, we generated a conditional mouse model in which oncogenic Kras(G12D) was activated specifically in lungs of young (3-5 months) and old (19-24 months) mice. Activation of Kras(G12D) in old mice resulted in shorter survival and development of higher-grade lung tumors. Six weeks after Kras(G12D) activation, old lung tissues contained higher numbers of adenomas than their young tissue counterparts...
October 18, 2017: Aging Cell
https://www.readbyqxmd.com/read/29046927/fdg-pet-ct-radiomics-for-predicting-the-outcome-of-locally-advanced-rectal-cancer
#12
Pierre Lovinfosse, Marc Polus, Daniel Van Daele, Philippe Martinive, Frédéric Daenen, Mathieu Hatt, Dimitris Visvikis, Benjamin Koopmansch, Frédéric Lambert, Carla Coimbra, Laurence Seidel, Adelin Albert, Philippe Delvenne, Roland Hustinx
PURPOSE: The aim of this study was to investigate the prognostic value of baseline (18)F-FDG PET/CT textural analysis in locally-advanced rectal cancer (LARC). METHODS: Eighty-six patients with LARC underwent (18)F-FDG PET/CT before treatment. Maximum and mean standard uptake values (SUVmax and SUVmean), metabolic tumoral volume (MTV), total lesion glycolysis (TLG), histogram-intensity features, as well as 11 local and regional textural features, were evaluated...
October 18, 2017: European Journal of Nuclear Medicine and Molecular Imaging
https://www.readbyqxmd.com/read/29045535/select-2-a-phase-ii-double-blind-randomised-placebo-controlled-study-to-assess-the-efficacy-of-selumetinib-plus-docetaxel-as-a-second-line-treatment-for-patients-with-advanced-or-metastatic-non-small-cell-lung-cancer
#13
J C Soria, A Fülöp, C Maciel, J R Fischer, G Girotto, S Lago, E Smit, G Ostoros, W E E Eberhardt, P Lishkovska, S Lovick, G Mariani, A McKeown, E Kilgour, P Smith, K Bowen, A Kohlmann, D J Carlile, P A Jänne
Background: Combination of selumetinib plus docetaxel provided clinical benefit in a previous Phase II trial for patients with KRAS-mutant advanced non-small cell lung cancer (NSCLC). The Phase II SELECT-2 trial investigated safety and efficacy of selumetinib plus docetaxel for patients with advanced or metastatic NSCLC. Patients and methods: Patients who had disease progression after first-line anti-cancer therapy were randomised (2:2:1) to selumetinib 75 mg BID plus docetaxel 60 mg/m2 or 75 mg/m2 (SEL+DOC 60; SEL+DOC 75), or placebo plus docetaxel 75 mg/m2 (PBO+DOC 75)...
October 3, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/29045530/tracking-evolution-of-aromatase-inhibitor-resistance-with-circulating-tumour-dna-analysis-in-metastatic-breast-cancer
#14
Charlotte Fribbens, Isaac Garcia Murillas, Matthew Beaney, Sarah Hrebien, Ben O'Leary, Lucy Kilburn, Karen Howarth, Michael Epstein, Emma Green, Nitzan Rosenfeld, Alistair Ring, Stephen Johnston, Nicholas Turner
Background: Selection of resistance mutations may play a major role in the development of endocrine resistance. ESR1 mutations are rare in primary breast cancer but have high prevalence in patients treated with aromatase inhibitors (AI) for advanced breast cancer. We investigated the evolution of genetic resistance to first line AI therapy using sequential ctDNA sampling in patients with advanced breast cancer. Patients and Methods: 83 patients on first line AI therapy for metastatic breast cancer were enrolled in a prospective study...
October 4, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/29045529/impact-of-genetic-variations-in-the-mapk-signaling-pathway-on-outcome-in-metastatic-colorectal-cancer-patients-treated-with-first-line-folfiri-and-bevacizumab-data-from-fire-3-and-tribe-trials
#15
M D Berger, S Stintzing, V Heinemann, D Yang, S Cao, Y Sunakawa, Y Ning, S Matsusaka, S Okazaki, Y Miyamoto, M Suenaga, M Schirripa, S Soni, W Zhang, A Falcone, F Loupakis, H-J Lenz
Background: The MAPK-interacting kinase 1 (MKNK1) is localized downstream of the RAS/RAF/ERK and the MAP3K1/MKK/p38 signaling pathway. Through phosphorylation MKNK1 regulates the function of eukaryotic translation initiation factor 4E, a key player in translational control, whose expression is often upregulated in metastatic colorectal cancer patients (mCRC). Preclinical data suggest that MKNK1 increases angiogenesis by upregulating angiogenic factors. We therefore hypothesize that variations in the MKNK1 gene predict outcome in mCRC patients treated with first-line FOLFIRI and bevacizumab (bev)...
August 2, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/29045505/surfaceome-profiling-enables-isolation-of-cancer-specific-exosomal-cargo-in-liquid-biopsies-from-pancreatic-cancer-patients
#16
J Castillo, V Bernard, F A San Lucas, K Allenson, M Capello, D U Kim, P Gascoyne, F C Mulu, B M Stephens, J Huang, H Wang, A A Momin, R O Jacamo, M Katz, R Wolff, M Javle, G Varadhachary, I I Wistuba, S Hanash, A Maitra, H Alvarez
Background: Detection of circulating tumor DNA (ctDNA) can be limited due to their relative scarcity in circulation, particularly while patients are actively undergoing therapy. Exosomes provide a vehicle through which cancer-specific material can be enriched from the compendium of circulating non-neoplastic tissue-derived nucleic acids. We performed a comprehensive profiling of the pancreatic ductal adenocarcinoma (PDAC) exosomal "surfaceome" in order to identify surface proteins that will render liquid biopsies amenable to cancer-derived exosome enrichment for downstream molecular profiling...
September 25, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/29044863/identification-of-somatic-genetic-alterations-in-ovarian-clear-cell-carcinoma-with-next-generation-sequencing
#17
Yusuke Shibuya, Hideki Tokunaga, Sakae Saito, Kazurou Shimokawa, Fumiki Katsuoka, Li Bin, Kaname Kojima, Masao Nagasaki, Masayuki Yamamoto, Nobuo Yaegashi, Jun Yasuda
Ovarian clear cell carcinoma (OCCC) is the most refractory subtype of ovarian cancer and more prevalent in Japanese than Caucasians (25% and 5% of all ovarian cancer, respectively). The aim of this study is to discover the genomic alterations that may cause OCCC and effective molecular targets for chemotherapy. Paired genomic DNAs of 48 OCCC tissues and corresponding non-cancerous tissues were extracted from formalin-fixed, paraffin embedded specimens collected between 2007 and 2015 at Tohoku University Hospital...
October 16, 2017: Genes, Chromosomes & Cancer
https://www.readbyqxmd.com/read/29043412/randomized-study-of-etirinotecan-pegol-versus-irinotecan-as-second-line-treatment-for-metastatic-colorectal-cancer
#18
Heinz-Josef Lenz, Philip Philip, Mark Saunders, Tatjana Kolevska, Kalyan Mukherjee, Leslie Samuel, Shailesh Bondarde, Tracy Dobbs, Mary Tagliaferri, Ute Hoch, Alison L Hannah, Maurice Berkowitz
PURPOSE: Etirinotecan pegol (EP) is a long-acting topoisomerase-I inhibitor designed to provide sustained exposure to SN-38 (active metabolite of irinotecan). This phase II study compared EP versus irinotecan as second-line treatment for KRAS-mutant, irinotecan-naïve, metastatic colorectal cancer (mCRC). METHODS: Patients were randomized to EP 145 mg/m(2) or irinotecan 350 mg/m(2) Q21d until disease progression/unacceptable toxicity. The primary endpoint was progression-free survival (PFS) with response determined by central radiologic review (RECIST version 1...
October 17, 2017: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/29038850/a-triplet-combination-with-capecitabine-oxaliplatin-irinotecan-xeloxiri-plus-cetuximab-as-first-line-therapy-for-patients-with-metastatic-colorectal-cancer-a-dose-escalation-study
#19
Yasushi Sato, Masahiro Hirakawa, Hiroyuki Ohnuma, Minoru Takahashi, Tetsuro Okamoto, Koichi Okamoto, Hiroshi Miyamoto, Naoki Muguruma, Tomohisa Furuhata, Ichiro Takemasa, Junji Kato, Tetsuji Takayama
PURPOSE: The addition of cetuximab to triplet chemotherapy can increase treatment efficacy for patients with metastatic colorectal cancer (mCRC). We explored the dose-limiting toxicity and feasibility of a triweekly capecitabine, oxaliplatin, irinotecan, plus cetuximab (XELOXIRI plus cetuximab) regimen in patients with wild-type KRAS mCRC. METHODS: Patients received oxaliplatin (100 mg/m(2), day 1), capecitabine (1700 mg/m(2) per day from day 2 to 15), irinotecan (100, 120, and 150 mg/m(2) for dose levels 1, 2, 3, respectively, on day 1), and cetuximab (400 mg/m(2), day 1 and, thereafter, 250 mg/m(2) every week), repeated every 3 weeks...
October 16, 2017: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/29038297/tumor-pdcd1lg2-pd-l2-expression-and-the-lymphocytic-reaction-to-colorectal-cancer
#20
Yohei Masugi, Reiko Nishihara, Tsuyoshi Hamada, Mingyang Song, Annacarolina da Silva, Keisuke Kosumi, Mancang Gu, Yan Shi, Wanwan Li, Li Liu, Daniel Nevo, Kentaro Inamura, Yin Cao, Xiaoyun Liao, Katsuhiko Nosho, Andrew T Chan, Marios Giannakis, Adam J Bass, F Stephen Hodi, Gordon J Freeman, Scott J Rodig, Charles S Fuchs, Zhi Rong Qian, Jonathan A Nowak, Shuji Ogino
Expression of the immune-checkpoint ligand CD274 (programmed cell death 1 ligand 1, PD-L1, from gene CD274) contributes to suppression of antitumor T cell-mediated immune response in various tumor types. However, the role of PDCD1LG2 (PD-L2, CD273, from gene PDCD1LG2) in the tumor microenvironment remains unclear. We hypothesized that tumor PDCD1LG2 expression might be inversely associated with lymphocytic reactions to colorectal cancer. We examined tumor PDCD1LG2 expression by immunohistochemistry in 823 colon and rectal carcinoma cases within two U...
October 16, 2017: Cancer Immunology Research
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