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https://www.readbyqxmd.com/read/28325292/sirna-encapsulated-hybrid-nanoparticles-target-mutant-k-ras-and-inhibit-metastatic-tumor-burden-in-a-mouse-model-of-lung-cancer
#1
Maryna Perepelyuk, Olubunmi Shoyele, Ruth Birbe, Chellappagounder Thangavel, Yi Liu, Robert B Den, Adam E Snook, Bo Lu, Sunday A Shoyele
There is an unmet need in the development of an effective therapy for mutant K-ras-expressing non-small-cell lung cancer (NSCLC). Although various small molecules have been evaluated, an effective therapy remains a dream. siRNAs have the potential to downregulate mutant K-ras both at the protein and mRNA levels. However, a safe and effective delivery of siRNAs to tumors remains a limitation to their translational application in the treatment of this highly debilitating disease. Here we developed a novel hybrid nanoparticle carrier for effective delivery of anti-mutant K-ras to NSCLC (AKSLHN)...
March 17, 2017: Molecular Therapy. Nucleic Acids
https://www.readbyqxmd.com/read/28322512/clinicopathological-and-prognostic-features-of-surgically-resected-pathological-stage-i-lung-adenocarcinoma-harboring-epidermal-growth-factor-receptor-and-k-ras-mutation
#2
Kaoru Kaseda, Keisuke Asakura, Akio Kazama, Yukihiko Ozawa
BACKGROUND: This study aimed to evaluate mutations of the epidermal growth factor receptor (EGFR) and K-ras genes and their clinicopathological and prognostic features in patients with resected pathological stage I adenocarcinoma. METHODS: We examined 224 patients with surgically resected lung adenocarcinoma and analyzed the prognostic and predictive value of these mutations in 162 patients with pathological stage I adenocarcinoma. RESULTS: Mutations of the EGFR and K-ras genes were detected in 100 (44...
March 21, 2017: Thoracic Cancer
https://www.readbyqxmd.com/read/28319809/abt-737-synergizes-with-cisplatin-bypassing-aberration-of-apoptotic-pathway-in-non-small-cell-lung-cancer
#3
Eun Young Kim, Ji Ye Jung, Arum Kim, Yoon Soo Chang, Se Kyu Kim
A subset of non-small cell lung cancer (NSCLC), which does not have a druggable driver mutation, is treated with platinum-based cytotoxic chemotherapy, but it develops resistance triggered by DNA damage responses. Here, we investigated the effect of activation of STAT3 by cisplatin on anti-apoptotic proteins and the effectiveness of a co-treatment with cisplatin and a BH3 mimetic, ABT-737. We analyzed the relationship between cisplatin and STAT3 pathway and effect of ABT-737, when combined with cisplatin in NSCLC cells and K-ras mutant mouse models...
March 17, 2017: Neoplasia: An International Journal for Oncology Research
https://www.readbyqxmd.com/read/28314765/no-back-seat-for-a-progression-event-k-ras-as-a-therapeutic-target-in-crc
#4
REVIEW
Emily J Poulin, Kevin M Haigis
KRAS is the most frequently mutated oncogene in human cancer and plays a central, although poorly understood, role in colorectal cancer (CRC) progression. In this issue of Genes & Development, Boutin and colleagues (pp. 370-382) present a new mouse model of CRC in which the expression of oncogenic K-RAS is regulated by doxycycline. Using this model, they demonstrate that continued expression of oncogenic K-RAS is required for the survival of primary and metastatic colon cancers and that oncogenic K-RAS activates TGF-β signaling to promote tumor invasion and metastasis...
February 15, 2017: Genes & Development
https://www.readbyqxmd.com/read/28286004/computational-modeling-reveals-that-signaling-lipids-modulate-the-orientation-of-k-ras4a-at-the-membrane-reflecting-protein-topology
#5
Zhen-Lu Li, Matthias Buck
The structural, dynamical, and functional characterization of the small GTPase K-Ras has become a research area of intense focus due to its high occurrence in human cancers. Ras proteins are only fully functional when they interact with the plasma membrane. Here we present all-atom molecular dynamics simulations (totaling 5.8 μs) to investigate the K-Ras4A protein at membranes that contain anionic lipids (phosphatidyl serine or phosphatidylinositol bisphosphate). We find that similarly to the homologous and highly studied K-Ras4B, K-Ras4A prefers a few distinct orientations at the membrane...
March 9, 2017: Structure
https://www.readbyqxmd.com/read/28283889/cf3doda-me-induces-apoptosis-degrades-sp1-and-blocks-the-transformation-phase-of-the-blebbishield-emergency-program
#6
Rikiya Taoka, Goodwin G Jinesh, Wenrui Xue, Stephen Safe, Ashish M Kamat
Cancer stem cells are capable of undergoing cellular transformation after commencement of apoptosis through the blebbishield emergency program in a VEGF-VEGFR2-dependent manner. Development of therapeutics targeting the blebbishield emergency program would thus be important in cancer therapy. Specificity protein 1 (Sp1) orchestrates the transcription of both VEGF and VEGFR2; hence, Sp1 could act as a therapeutic target. Here, we demonstrate that CF3DODA-Me induced apoptosis, degraded Sp1, inhibited the expression of multiple drivers of the blebbishield emergency program such as VEGFR2, p70S6K, and N-Myc through activation of caspase-3, inhibited reactive oxygen species; and inhibited K-Ras activation to abolish transformation from blebbishields as well as transformation in soft agar...
March 11, 2017: Apoptosis: An International Journal on Programmed Cell Death
https://www.readbyqxmd.com/read/28259994/overexpression-of-wild-type-p21ras-plays-a-prominent-role-in-colorectal-cancer
#7
Shuang Bai, Qiang Feng, Xin-Yan Pan, Hong Zou, Hao-Bin Chen, Peng Wang, Xin-Liang Zhou, Yan-Ling Hong, Shu-Ling Song, Ju-Lun Yang
Colorectal cancer (CRC) is the most common gastrointestinal type of cancer. The overexpression of Ras proteins, particularly p21Ras, are involved in the development of CRC. However, the subtypes of the p21Ras proteins that are overexpressed and the mutation status remain unknown restricting the development of therapeutic antibodies targeting p21Ras proteins. The present study aimed to investigate the mutation status of ras genes associated with Ras proteins that are overexpressed in CRC and explore whether or not wild-type p21Ras could be a target for CRC therapy...
February 21, 2017: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/28259593/using-an-endoscopic-distal-cap-to-collect-pancreatic-fluid-from-the-ampulla-with-video
#8
Masaya Suenaga, Yoshihiko Sadakari, Jose Alejandro Almario, Michael Borges, Anne-Marie Lennon, Eun-Ji Shin, Marcia Irene Canto, Michael Goggins
BACKGROUND AND AIMS: Duodenal collections of pancreatic fluid can be used as a source of mutations and other markers of pancreatic ductal neoplasia, but admixing pancreatic juice with duodenal contents lowers the concentrations of mutations. Collecting pancreatic fluid directly from the ampulla could yield a purer sample of pancreatic fluid. METHODS: We used an endoscopic distal cap attachment to "cap" the ampulla and collect secretin-stimulated pancreatic fluid samples for 5 minutes from 81 patients undergoing pancreatic evaluation as part of the Cancer of the Pancreas Screening studies...
March 1, 2017: Gastrointestinal Endoscopy
https://www.readbyqxmd.com/read/28259298/the-cornerstone-k-ras-mutation-in-pancreatic-adenocarcinoma-from-cell-signaling-network-target-genes-biological-processes-to-therapeutic-targeting
#9
REVIEW
Nicolas Jonckheere, Romain Vasseur, Isabelle Van Seuningen
RAS belongs to the super family of small G proteins and plays crucial roles in signal transduction from membrane receptors in the cell. Mutations of K-RAS oncogene lead to an accumulation of GTP-bound proteins that maintains an active conformation. In the pancreatic ductal adenocarcinoma (PDAC), one of the most deadly cancers in occidental countries, mutations of the K-RAS oncogene are nearly systematic (>90%). Moreover, K-RAS mutation is the earliest genetic alteration occurring during pancreatic carcinogenetic sequence...
March 2017: Critical Reviews in Oncology/hematology
https://www.readbyqxmd.com/read/28252958/mixed-probe-simulation-and-probe-derived-surface-topography-map-analysis-for-ligand-binding-site-identification
#10
Abdallah Sayyed-Ahmad, Alemayehu A Gorfe
Membrane proteins represent a considerable fraction of pharmaceutical drug targets. A computational technique to identify ligand binding pockets in these proteins is therefore of great importance. We recently reported such a technique called pMD-membrane that utilizes small molecule probes to detect ligand binding sites and surface hotspots on membrane proteins based on probe-based molecular dynamics simulation. The current work extends pMD-membrane to a diverse set of small organic molecular species that can be used as cosolvents during simulation of membrane proteins...
March 13, 2017: Journal of Chemical Theory and Computation
https://www.readbyqxmd.com/read/28246467/familial-pancreatic-cancer-concept-management-and-issues
#11
REVIEW
Hiroyuki Matsubayashi, Kyoichi Takaori, Chigusa Morizane, Hiroyuki Maguchi, Masamichi Mizuma, Hideaki Takahashi, Keita Wada, Hiroko Hosoi, Shinichi Yachida, Masami Suzuki, Risa Usui, Toru Furukawa, Junji Furuse, Takamitsu Sato, Makoto Ueno, Yoshimi Kiyozumi, Susumu Hijioka, Nobumasa Mizuno, Takeshi Terashima, Masaki Mizumoto, Yuzo Kodama, Masako Torishima, Takahisa Kawaguchi, Reiko Ashida, Masayuki Kitano, Keiji Hanada, Masayuki Furukawa, Ken Kawabe, Yoshiyuki Majima, Toru Shimosegawa
Familial pancreatic cancer (FPC) is broadly defined as two first-degree-relatives with pancreatic cancer (PC) and accounts for 4%-10% of PC. Several genetic syndromes, including Peutz-Jeghers syndrome, hereditary pancreatitis, hereditary breast-ovarian cancer syndrome (HBOC), Lynch syndrome, and familial adenomatous polyposis (FAP), also have increased risks of PC, but the narrowest definition of FPC excludes these known syndromes. When compared with other familial tumors, proven genetic alterations are limited to a small proportion (< 20%) and the familial aggregation is usually modest...
February 14, 2017: World Journal of Gastroenterology: WJG
https://www.readbyqxmd.com/read/28239030/metabolic-profiling-of-gemcitabine-and-paclitaxel-treated-immortalized-human-pancreatic-cell-lines-with-k-ras-g12d
#12
Akiko Todaka, Rina Umehara, Keiko Sasaki, Masakuni Serizawa, Kenichi Urakami, Masatoshi Kusuhara, Ken Yamaguchi, Hirofumi Yasui
The mechanisms of action of gemcitabine (GEM) and paclitaxel (PTX) have been well investigated, and shown to be the inhibition of DNA polymerase and polymerization of tubulin, respectively. Meanwhile, genomic research has revealed that mutations in the K-RAS oncogene occur in over 90% of pancreatic cancer. Oncogenic alteration rewires alternative metabolic pathways to satisfy the demands of growth. The K-RAS oncogene also has been shown to upregulate glycolysis and glutaminolysis. However, it is still unclear whether K-RAS independently plays a central role in controlling tumor metabolism...
2017: Biomedical Research
https://www.readbyqxmd.com/read/28218784/mutations-in-codons-12-and-13-of-k-ras-exon-2-in-colorectal-tumors-of-saudi-arabian-patients-frequency-clincopathological-associations-and-clinical-outcomes
#13
J Zekri, A Al-Shehri, M Mahrous, S Al-Rehaily, T Darwish, S Bassi, H El Taani, A Al Zahrani, S Elsamany, J Al-Maghrabi, B B Sadiq
Mutations in codons 12/13 of K-ras exon 2 are associated with reduced benefit from anti-epidermal growth factor receptor antibody treatment for metastatic colorectal cancer (CRC). Here, we evaluated the frequency of K-ras mutations and their relationship with clinicopathological features and treatment outcomes in Saudi Arabian patients with CRC. The genetic status of K-ras was determined in 300 patients diagnosed with CRC. Clinical information was collected retrospectively. K-ras was wild-type in 58% and mutated in 42% of the tumors...
February 16, 2017: Genetics and Molecular Research: GMR
https://www.readbyqxmd.com/read/28209717/autophagy-metabolism-and-cancer
#14
Jessie Yanxiang Guo, Eileen White
Macroautophagy (autophagy hereafter) is a process that collects cytoplasmic components, particularly mitochondria, and degrades them in lysosomes. In mammalian systems, basal autophagy levels are normally low but are profoundly stimulated by starvation and essential for survival. Cancer cells up-regulate autophagy and can be more autophagy-dependent than most normal tissues. Genetic deficiency in essential autophagy genes in tumors in many autochthonous mouse models for cancer reduces tumor growth. In K-ras(G12D)-driven non-small cell lung cancer (NSCLC) and other models, autophagy sustains metabolism and survival...
February 16, 2017: Cold Spring Harbor Symposia on Quantitative Biology
https://www.readbyqxmd.com/read/28197787/dermatux-phase-iv-trial-of-cetuximab-plus-folfiri-in-first-line-metastatic-colorectal-cancer-receiving-a-pre-defined-skin-care
#15
Carl Christoph Schimanski, Frank Staib, Thomas Göhler, Holger Hebart, Michael Heike, Michael Neise, Jochen Rudi, Thomas Geer, Gerrit Dingeldein, Claudia Lang, Peter Ehscheidt, Thomas Flohr, Klaus Maria Josten, Meinolf Karthaus, Alexander Schmittel, Jan Wierecky, Emil Boller, Martin Indorf, Marcus-Alexander Wörns, Peter R Galle, Markus Moehler
PURPOSE: Cetuximab-induced skin rash Gd3+ occurs in ≥16% patients (pts) (Heinemann et al., Lancet Oncol 15(10):1065-1075, 2014; Van Cutsem et al. J Clin Oncol 27(19):3117-25; 2009b). Survival, response, and toxicity parameters were re-evaluated under a pre-defined skin prophylaxis consistent of vitamin K1 ointment and oral doxycycline. METHODS: This is a national, multicenter, phase 4, first-line mCRC (K-RAS wt) trial. Pts received irinotecan 180 mg/m² (d1), FA 400 mg/m² (d1), 5-FU 400 mg/m² (d1), 5-FU 2400 mg/m² (d1-2), and cetuximab [400 mg/m² (d1), and then 250 mg/m² qw], prophylactic 0...
February 14, 2017: Journal of Cancer Research and Clinical Oncology
https://www.readbyqxmd.com/read/28193718/h-ras-isoform-mediates-protection-against-pressure-overload-induced-cardiac-dysfunction-in-part-through-activation-of-akt
#16
Takahisa Matsuda, Jae Im Jeong, Shohei Ikeda, Takanobu Yamamoto, Shumin Gao, Gopal J Babu, Peiyong Zhai, Dominic P Del Re
BACKGROUND: In general, Ras proteins are thought to promote cardiac hypertrophy, an important risk factor for cardiovascular disease and heart failure. However, the contribution of different Ras isoforms has not been investigated. The objective of this study was to define the role of H- and K-Ras in modulating stress-induced myocardial hypertrophy and failure. METHODS AND RESULTS: We used H- and K-Ras gene knockout mice and subjected them to pressure overload to induce cardiac hypertrophy and dysfunction...
February 2017: Circulation. Heart Failure
https://www.readbyqxmd.com/read/28188446/treatment-options-for-egfr-t790m-negative-egfr-tyrosine-kinase-inhibitor-resistant-non-small-cell-lung-cancer
#17
Salvatore Corallo, Ettore D'Argento, Antonia Strippoli, Michele Basso, Santa Monterisi, Sabrina Rossi, Alessandra Cassano, Carlo M Barone
The introduction of first- and second-generation EGFR-tyrosine kinase inhibitors (TKIs) (gefitinib, erlotinib and afatinib) for the treatment of advanced EGFR-mutant non-small cell lung cancer (NSCLC) has dramatically improved patients' prognosis and quality of life (QoL). Unfortunately, after an initial and sometimes durable benefit from EGFR-TKI therapy, all patients with EGFR-mutant lung cancer eventually become resistant to the treatment and experience disease progression. In approximately 50% of these patients, genomic alterations in the EGFR kinase domain resulting in the mutant T790M are responsible for the resistance and this has led to the development of novel EGFR inhibitors active against mutant-T790M EGFR...
February 10, 2017: Targeted Oncology
https://www.readbyqxmd.com/read/28188432/correlations-of-igf-1r-and-cox-2-expressions-with-ras-and-braf-genetic-mutations-clinicopathological-features-and-prognosis-of-colorectal-cancer-patients
#18
Mei Jin, Zi-Wen Long, Jing Yang, Xiang Lin
This case-control study aims to investigate the correlations of insulin-like growth factor receptor 1 (IGF-1R) and cyclooxygenase 2 (COX-2) expressions with Ras and BRAF genetic mutations, clinicopathological features and prognosis of colorectal cancer (CRC) patients. A total of 213 CRC patients (case group) and 200 healthy individuals (control group) were selected from our hospital. Ras (K-Ras/N-Ras) and BRAF genetic mutations were detected by direct sequencing. The positive expression rates of IGF-IR and COX-2 in CRC and normal tissues were detected using immunohistochemistry...
February 10, 2017: Pathology Oncology Research: POR
https://www.readbyqxmd.com/read/28169239/modified-mismatch-polymerase-chain-reaction-restriction-fragment-length-polymorphism-detected-mutations-in-codon-12-and-13-of-exon-2-of-k-ras-gene-in-colorectal-cancer-patients-and-its-association-with-liver-metastases-data-from-a-south-asian-country
#19
Fathima Dhilhani Mohamed Faleel, M I M De Zoysa, M D S Lokuhetti, Y I N S Gunawardena, Vishvanath Naduviladath Chandrasekharan, Ranil Samantha Dassanayake
AIM: Mutations in K-ras codon 12 and 13 of exon 2 are known to affect prognosis and impart resistance to anti-epidermal growth factor monoclonal antibody therapy in colorectal carcinoma (CRC). Our aim was to investigate the utility value of modified mismatch polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay to detect mutation in K-ras codons of CRC patients and to relate the mutational status to liver metastasis. METHODOLOGY: Mismatch PCR-RFLP was developed to detect K-ras mutations in DNA isolated from paraffinized tumor tissue of thirty CRC patients...
October 2016: Journal of Cancer Research and Therapeutics
https://www.readbyqxmd.com/read/28162998/common-telomere-changes-during-in%C3%A2-vivo-reprogramming-and-early-stages-of-tumorigenesis
#20
Rosa M Marión, Isabel López de Silanes, Lluc Mosteiro, Benjamin Gamache, María Abad, Carmen Guerra, Diego Megías, Manuel Serrano, Maria A Blasco
Reprogramming of differentiated cells into induced pluripotent stem cells has been recently achieved in vivo in mice. Telomeres are essential for chromosomal stability and determine organismal life span as well as cancer growth. Here, we study whether tissue dedifferentiation induced by in vivo reprogramming involves changes at telomeres. We find telomerase-dependent telomere elongation in the reprogrammed areas. Notably, we found highly upregulated expression of the TRF1 telomere protein in the reprogrammed areas, which was independent of telomere length...
February 14, 2017: Stem Cell Reports
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