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https://www.readbyqxmd.com/read/29165690/the-regulatory-g4-motif-of-the-kirsten-ras-kras-gene-is-sensitive-to-guanine-oxidation-implications-on-transcription
#1
Susanna Cogoi, Annalisa Ferino, Giulia Miglietta, Erik B Pedersen, Luigi E Xodo
KRAS is one of the most mutated genes in human cancer. It is controlled by a G4 motif located upstream of the transcription start site. In this paper, we demonstrate that 8-oxoguanine (8-oxoG), being more abundant in G4 than in non-G4 regions, is a new player in the regulation of this oncogene. We designed oligonucleotides mimicking the KRAS G4-motif and found that 8-oxoG impacts folding and stability of the G-quadruplex. Dimethylsulphate-footprinting showed that the G-run carrying 8-oxoG is excluded from the G-tetrads and replaced by a redundant G-run in the KRAS G4-motif...
November 20, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/29154079/clinical-performance-of-a-next-generation-sequencing-assay-thyroseq-v2-in-the-evaluation-of-indeterminate-thyroid-nodules
#2
Aida Taye, Dillon Gurciullo, Brett A Miles, Ashita Gupta, Randall P Owen, William B Inabnet, Jessica N Beyda, Jennifer L Marti
BACKGROUND: Molecular testing with the Thyroseq v2 next generation sequencing panel ("Thyroseq") is used to estimate the risk of cancer in indeterminate thyroid nodules. METHODS: We analyzed 156 indeterminate thyroid nodules evaluated with Thyroseq, across 3 institutions. Thyroseq data and surgical pathology were matched via pathologic re-review. A result was considered Thyroseq positive if molecular alterations were annotated on the report with malignancy probability >30%...
November 16, 2017: Surgery
https://www.readbyqxmd.com/read/29141318/-ras-associated-autoimmune-leukoproliferative-disorder-a-report-of-2-cases-and-literature-review
#3
T Y He, C R Li, Y Xia, F F Liang, Y Luo, J Yang
Objective: To investigate the clinical features and genetic characteristics of cases with Ras-associated autoimmune leukoproliferative disorder(RALD). Method: Characteristics of clinical data and gene mutation of the first two cases in China with RALD were retrospectively analyzed. The related literature was searched by using search terms "NRAS" , "KRAS" or "RALD" . Result: Case1, a seven-year-seven-month old girl, was admitted due to "thrombocytopenia and splenomegaly for three years" . Palpation showed enlargement of submandibular lymph nodes and hepatosplenomegaly...
November 2, 2017: Zhonghua Er Ke za Zhi. Chinese Journal of Pediatrics
https://www.readbyqxmd.com/read/29140695/rna-g-quadruplexes-in-kirsten-ras-kras-oncogene-as-targets-for-small-molecules-inhibiting-translation
#4
Giulia Miglietta, Susanna Cogoi, Jessica Marinello, Giovanni Capranico, Alexander S Tikhomirov, Andrey E Shchekotikhin, Luigi E Xodo
The human KRAS transcript contains a G-rich 5'-UTR sequence (77 % GC) harbouring several G4 motifs capable to form stable RNA G-quadruplex (RG4) structures that can serve as targets for small molecules. A biotin-streptavidin pull-down assay showed that 4,11-bis(2-aminoethylamino)anthra[2,3-b]furan-5,10-dione (2a) binds to RG4s in the KRAS transcript under low-abundance cellular conditions. Dual-luciferase assays demonstrated that 2a and its analogue 4,11-bis(2-aminoethylamino)anthra[2,3-b]thiophene-5,10-dione 2b) repress translation in a dose-dependent manner...
November 15, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29137434/involment-of-ras-erk1-2-signaling-and-mef2c-in-mir-155-3p-inhibition-triggered-cardiomyocyte-differentiation-of-embryonic-stem-cell
#5
Xiang Ling, Dongbo Yao, Lumei Kang, Jing Zhou, Ying Zhou, Hui Dong, Keping Zhang, Lei Zhang, Hongping Chen
MicroRNAs (miRNAs) are short, noncoding RNAs that regulate post-transcriptional gene expression by targeting messenger RNAs (mRNAs) for cleavage or translational repression. Growing evidence indicates that miR-155 expression changes with the development of heart and plays an important role in heart physiopathology. However, the role of miR-155 in cardiac cells differentiation is unclear. Using the well-established embryonic stem cell (ESC), we demonstrated that miR-155-3p expression was down-regulated during cardiogenesis from mouse ESC...
October 13, 2017: Oncotarget
https://www.readbyqxmd.com/read/29129745/fluorescent-light-up-acridine-orange-derivatives-bind-and-stabilize-kras-22rt-g-quadruplex
#6
Josué Carvalho, Edgar Pereira, Julien Marquevielle, Maria P C Campello, Jean-Louis Mergny, António Paulo, Gilmar F Salgado, João A Queiroz, Carla Cruz
KRAS is often found mutated in lethal cancers and should be an important target for anticancer drug development. However, no effective inhibitor has been reported so far, prompting the scientific community to describe the RAS proteins as nearly "undruggable". Recent approaches developed to modulate KRAS protein expression comprises the targeting of G-quadruplex (G4) structures formed within the nuclease hypersensitive element of KRAS promoter region, by designing small and specific ligands to stabilize the tertiary fold and reduce gene expression...
November 9, 2017: Biochimie
https://www.readbyqxmd.com/read/29129563/da-raf-a-dominant-negative-antagonist-of-the-ras-erk-pathway-is-a-putative-tumor-suppressor
#7
Emiri Kanno, Osamu Kawasaki, Kazuya Takahashi, Kazunori Takano, Takeshi Endo
Activating mutations of RAS genes, particularly KRAS, are detected with high frequency in human tumors. Mutated Ras proteins constitutively activate the ERK pathway (Raf-MEK-ERK phosphorylation cascade), leading to cellular transformation and tumorigenesis. DA-Raf1 (DA-Raf) is a splicing variant of A-Raf and contains the Ras-binding domain (RBD) but lacks the kinase domain. Accordingly, DA-Raf antagonizes the Ras-ERK pathway in a dominant-negative fashion and suppresses constitutively activated K-Ras-induced cellular transformation...
November 9, 2017: Experimental Cell Research
https://www.readbyqxmd.com/read/29127119/rasa1-and-nf1-are-preferentially-co-mutated-and-define-a-distinct-genetic-subset-of-smokingassociated-non-small-cell-lung-carcinomas-sensitive-to-mek-inhibition
#8
Takuo Hayashi, Patrice Desmeules, Roger S Smith, Alexander Drilon, Romel Somwar, Marc Ladanyi
PURPOSE: Ras-GTPase activating proteins (RasGAPs), notably NF1 and RASA1, mediate negative control of the RAS/MAPK pathway. We evaluated clinical and molecular characteristics of NSCLC with RASA1 mutations in comparison with NF1-mutated cases. EXPERIMENTAL DESIGN: Large genomic datasets of NSCLC [MSK-IMPACT™ dataset at MSKCC (n=2004), TCGA combined lung cancer dataset (n=1144)] were analyzed to define concurrent mutations and clinical features of RASA1-mutated NSCLCs...
November 10, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29126344/genetic-and-epigenetic-of-medullary-thyroid-cancer
#9
Fatemeh Khatami, Seyed Mohammad Tavangar
Medullary thyroid carcinoma (MTC) is an infrequent, calcitonin producing neuroendocrine tumor and initiates from the parafollicular C cells of the thyroid gland. Several genetic and epigenetic alterations are collaterally responsible for medullary thyroid carcinogenesis. In this review article, we shed light on all the genetic and epigenetic hallmarks of MTC. From the genetic perspective, RET, HRAS, and KRAS are the most important genes that are characterized in MTC. From the epigenetic perspective, Ras-association domain family member 1A, telomerase reverse transcriptase promoter methylations, overexpression of histone methyltransferases, EZH2 and SMYD3, and wide ranging increase and decrease in non-coding RNAs can be responsible for medullary thyroid carcinogenesis...
November 11, 2017: Iranian Biomedical Journal
https://www.readbyqxmd.com/read/29117520/phosphorylated-calmodulin-promotes-pi3k-activation-by-binding-to-the-sh2-domains
#10
Mingzhen Zhang, Hyunbum Jang, Vadim Gaponenko, Ruth Nussinov
How calmodulin (CaM) acts in KRAS-driven cancers is a vastly important question. CaM binds to and stimulates PI3Kα/Akt signaling, promoting cell growth and proliferation. Phosphorylation of CaM at Tyr(99) (pY99) enhances PI3Kα activation. PI3Kα is a lipid kinase. It phosphorylates PIP2 to produce PIP3, to which Akt binds. PI3Kα has two subunits: the regulatory p85 and the catalytic p110. Here, exploiting explicit-solvent MD simulations we unveil key interactions between phosphorylated CaM (pCaM) and the two SH2 domains in the p85 subunit, confirm experimental observations, and uncover PI3Kα's mechanism of activation...
November 7, 2017: Biophysical Journal
https://www.readbyqxmd.com/read/29113235/dysregulation-of-kras-signaling-in-pancreatic-cancer-is-not-associated-with-kras-mutations-and-outcome
#11
Radmila Lemstrova, Veronika Brynychova, David J Hughes, Viktor Hlavac, Pavel Dvorak, Joanne E Doherty, Helena A Murray, Martin Crockard, Martin Oliverius, Jan Hlavsa, Eva Honsova, Jan Mazanec, Zdenek Kala, Martin Lovecek, Roman Havlik, Jiri Ehrmann, Ondrej Strouhal, Pavel Soucek, Bohuslav Melichar, Beatrice Mohelnikova-Duchonova
Pancreatic ductal adenocarcinoma (PDAC) is a tumor with a poor prognosis, and no targeted therapy is currently available. The aim of the present study was to investigate the prognostic significance of the expression of V-Ki-ras2 Κirsten rat sarcoma viral oncogene homolog (KRAS), downstream signaling pathway genes and the association with clinical characteristics in PDAC patients undergoing radical surgery. Tumors and adjacent non-neoplastic pancreatic tissues were examined in 45 patients with histologically verified PDAC...
November 2017: Oncology Letters
https://www.readbyqxmd.com/read/29112457/fosl1-promotes-kras-induced-lung-cancer-through-amphiregulin-and-cell-survival-gene-regulation
#12
Indira M Elangovan, Michelle Vaz, Chandramohan R Tamatam, Haranatha R Potteti, Narsa M Reddy, Sekhar P Reddy
RATIONALE: FOSL1/AP-1 transcription factor regulates gene expression controlling various pathophysiological processes. It is a major effector of RAS-ERK1/2 signaling and activated in human lung epithelia by tumorigenic stimuli. Recent evidence shows an inverse correlation between FOSL1 expression and the survival of lung cancer patients with adenocarcinomas; however its role in lung tumorigenesis remains elusive. OBJECTIVES: To determine the role of FOSL1 in Kras-induced lung adenocarcinoma in vivo, and its downstream effector mechanisms...
November 7, 2017: American Journal of Respiratory Cell and Molecular Biology
https://www.readbyqxmd.com/read/29111094/real-time-pcr-based-method-for-the-rapid-detection-of-extended-ras-mutations-using-bridged-nucleic-acids-in-colorectal-cancer
#13
Takao Iida, Yukie Mizuno, Yasuharu Kaizaki
Mutations in RAS and BRAF are predictors of the efficacy of anti-epidermal growth factor receptor (EGFR) therapy in patients with metastatic colorectal cancer (mCRC). Therefore, simple, rapid, cost-effective methods to detect these mutations in the clinical setting are greatly needed. In the present study, we evaluated BNA Real-time PCR Mutation Detection Kit Extended RAS (BNA Real-time PCR), a real-time PCR method that uses bridged nucleic acid clamping technology to rapidly detect mutations in RAS exons 2-4 and BRAF exon 15...
October 27, 2017: Clinica Chimica Acta; International Journal of Clinical Chemistry
https://www.readbyqxmd.com/read/29101115/efforts-to-develop-kras-inhibitors
#14
Matthew Holderfield
The high prevalence of KRAS mutations in human cancers and the lack of effective treatments for patients ranks KRAS among the most highly sought-after targets for preclinical oncologists. Pharmaceutical companies and academic laboratories have tried for decades to identify small molecule inhibitors of oncogenic KRAS proteins, but little progress has been made and many have labeled KRAS undruggable. However, recent progress in in silico screening, fragment-based drug design, disulfide tethered screening, and some emerging themes in RAS biology have caused the field to reconsider previously held notions about targeting KRAS...
November 3, 2017: Cold Spring Harbor Perspectives in Medicine
https://www.readbyqxmd.com/read/29089332/chemopreventive-and-antitumor-efficacy-of-curcumin-in-a-spontaneously-developing-hen-ovarian-cancer-model
#15
Kazim Sahin, Cemal Orhan, Mehmet Tuzcu, Nurhan Sahin, Hakki Tastan, Ibrahim Hanifi Ozercan, Osman Guler, Nermin Kahraman, Omer Kucuk, Bulent Ozpolat
We investigated the effect of daily dietary curcumin intake on the development and progression of spontaneous ovarian cancer in a galline (hen) model, as the chicken is the only nonhuman animal in which ovarian cancer spontaneously develops with a high prevalence. At the end of 12 months, ovarian cancer had spontaneously developed in 39% (35/90) of control hens not fed curcumin (n = 90). In comparison, it spontaneously developed in 27% (24/90) and 17% (15/90) of hens given curcumin at 25.8 (n=90) and 53.0 mg/day (n=90), respectively (P = 0...
October 31, 2017: Cancer Prevention Research
https://www.readbyqxmd.com/read/29079711/histone-deacetylase-inhibition-enhances-the-antitumor-activity-of-a-mek-inhibitor-in-lung-cancer-cells-harboring-ras-mutations
#16
Tadaaki Yamada, Joseph M Amann, Azusa Tanimoto, Hirokazu Taniguchi, Takehito Shukuya, Cynthia Timmers, Seiji Yano, Konstantin Shilo, David P Carbone
Non-small-cell lung cancer (NSCLC) can be identified by precise molecular subsets based on genomic alterations that drive tumorigenesis and include mutations in EGFR, KRAS, and various ALK fusions. However, despite effective treatments for EGFR and ALK, promising therapeutics have not been developed for patients with KRAS mutations. It has been reported that one way the RAS-ERK pathway contributes to tumorigenesis is by affecting stability and localization of FOXO3a protein, an important regulator of cell death and the cell cycle...
October 27, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29075780/association-of-tumor-her3-messenger-rna-expression-with-panitumumab-efficacy-in-advanced-colorectal-cancer
#17
Jenny F Seligmann, Ace J Hatch, Susan D Richman, Faye Elliott, Bart Jacobs, Sarah Brown, Herbert Hurwitz, Jennifer H Barrett, Philip Quirke, Andrew B Nixon, Matthew T Seymour
Importance: Epidermal growth factor receptor (EGFR) (HER1) signaling depends on ligand binding and dimerization with itself or other HER receptors. We previously showed in a randomized trial that high EGFR ligand expression is predictive of panitumumab benefit in advanced colorectal cancer. Tumor expression of HER3 may further refine the RAS wild-type (wt) population benefitting from anti-EGFR agents. Objective: To examine HER3 messenger RNA expression as a prognostic and predictive biomarker for anti-EGFR therapy in a randomized clinical trial of panitumumab...
October 26, 2017: JAMA Oncology
https://www.readbyqxmd.com/read/29061646/kras-mutation-and-consensus-molecular-subtypes-2-and-3-are-independently-associated-with-reduced-immune-infiltration-and-reactivity-in-colorectal-cancer
#18
Neeraj Lal, Brian S White, Ghaleb Goussous, Oliver J Pickles, Michael Mason, Andrew D Beggs, Philippe Taniere, Benjamin E Willcox, Justin Guinney, Gary Middleton
PURPOSE: KRAS mutation is a common canonical mutation in CRC, found at differing frequencies in all Consensus Molecular Subtypes (CMS). The independent immunobiological impacts of RAS mutation and CMS are unknown. Thus, we explored the immunobiological effects of KRAS mutation across the CMS spectrum. EXPERIMENTAL DESIGN: Transcriptional analysis of immune genes/signatures was performed with RNA-seq using The Cancer Genome Atlas (TCGA) and the KFSYSCC data set. Multivariate analysis included KRAS status, CMS, tumour location, MSI status, and neoantigen load...
October 23, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29059158/raf-inhibitor-ly3009120-sensitizes-ras-or-braf-mutant-cancer-to-cdk4-6-inhibition-by-abemaciclib-via-superior-inhibition-of-phospho-rb-and-suppression-of-cyclin-d1
#19
S-H Chen, X Gong, Y Zhang, R D Van Horn, T Yin, L Huber, T F Burke, J Manro, P W Iversen, W Wu, S V Bhagwat, R P Beckmann, R V Tiu, S G Buchanan, S-B Peng
KRAS, NRAS and BRAF mutations are among the most important oncogenic drivers in many major cancer types, such as melanoma, lung, colorectal and pancreatic cancer. There is currently no effective therapy for the treatment of RAS mutant cancers. LY3009120, a pan-RAF and RAF dimer inhibitor advanced to clinical study has been shown to inhibit both RAS and BRAF mutant cell proliferation in vitro and xenograft tumor growth in vivo. Abemaciclib, a CDK4/6-selective inhibitor, is currently in phase III studies for ER-positive breast cancer and KRAS mutant lung cancer...
October 23, 2017: Oncogene
https://www.readbyqxmd.com/read/29058260/progression-free-survival-in-patients-receiving-chemotherapy-alone-c-or-chemotherapy-with-bevacizumab-cb-for-first-line-treatment-of-kras-mutant-metastatic-colorectal-cancer-in-community-oncology-settings
#20
Arthur C Houts, Sarika Ogale, Yousuf Zafar, Joleen M Hubbard, Sacha Satram-Hoang, Nicolas Sommer, Mark S Walker
PURPOSE: Bevacizumab is a standard first-line (L1) treatment for metastatic colorectal cancer (mCRC) patients regardless of RAS status. This retrospective study examined treatment patterns and outcomes in a community oncology sample of KRAS mutant mCRC patients treated with chemotherapy (C) or C plus bevacizumab (CB) in L1. METHODS: This study used medical records from the Vector Oncology Data Warehouse. Eligible patients were confirmed KRAS mutant mCRC and received L1 C or CB...
October 23, 2017: Journal of Gastrointestinal Cancer
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