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https://www.readbyqxmd.com/read/28239030/metabolic-profiling-of-gemcitabine-and-paclitaxel-treated-immortalized-human-pancreatic-cell-lines-with-k-ras-g12d
#1
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
#2
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
#3
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
#4
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
#5
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
#6
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
#7
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
#8
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
#9
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
https://www.readbyqxmd.com/read/28153726/k-ras-g12d-selective-inhibitory-peptides-generated-by-random-peptide-t7-phage-display-technology
#10
Kotaro Sakamoto, Yusuke Kamada, Tomoya Sameshima, Masahiro Yaguchi, Ayumu Niida, Shigekazu Sasaki, Masanori Miwa, Shoichi Ohkubo, Jun-Ichi Sakamoto, Masahiro Kamaura, Nobuo Cho, Akiyoshi Tani
Amino-acid mutations of Gly(12) (e.g. G12D, G12V, G12C) of V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (K-Ras), the most promising drug target in cancer therapy, are major growth drivers in various cancers. Although over 30 years have passed since the discovery of these mutations in most cancer patients, effective mutated K-Ras inhibitors have not been marketed. Here, we report novel and selective inhibitory peptides to K-Ras(G12D). We screened random peptide libraries displayed on T7 phage against purified recombinant K-Ras(G12D), with thorough subtraction of phages bound to wild-type K-Ras, and obtained KRpep-2 (Ac-RRCPLYISYDPVCRR-NH2) as a consensus sequence...
March 11, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28133294/-a-case-of-rectal-cancer-with-unresectable-liver-metastasis-responding-to-rechallenge-with-folfiri
#11
Mariko Kamiya, Katsuya Yoneyama, Yuki Doi, Junya Shirai, Yoshihiro Suzuki, Shinsuke Hatori, Takanobu Yamada, Tsutomu Sato, Naoto Yamamoto, Takashi Oshima, Norio Yukawa, Takaki Yoshikawa, Yasushi Rino, Munetaka Masuda
A 63-year-old man underwent low anterior resection for rectal cancer.A synchronous liver metastasis located in segment 8 was 12 cm in diameter and unresectable due to its proximity to the inferior vena cava(IVC).The postoperative pathological findings revealed a T3(SS), N0, M1(liver)Stage IV tumor, and wild type K-RAS was expressed.We chose FOLFIRI plus cetuximab(Cmab)for first-line chemotherapy.After 6 courses, we changed the molecular target drug from Cmab to bevacizumab( Bmab)because the liver metastasis remained unresectable...
November 2016: Gan to Kagaku Ryoho. Cancer & Chemotherapy
https://www.readbyqxmd.com/read/28122482/identification-of-differentially-expressed-k-ras-transcript-variants-in-patients-with-leiomyoma
#12
Nooshin Zolfaghari, Shirin Shahbazi, Mahnaz Torfeh, Maryam Khorasani, Mehrdad Hashemi, Reza Mahdian
PURPOSE: Molecular studies have demonstrated a wide range of gene expression variations in uterine leiomyoma. The rat sarcoma virus/rapidly accelerated fibrosarcoma/mitogen-activated protein kinase (RAS/RAF/MAPK) is the crucial cellular pathway in transmitting external signals into nucleus. Deregulation of this pathway contributes to excessive cell proliferation and tumorigenesis. The present study aims to investigate the expression profile of the K-Ras transcripts in tissue samples from patients with leiomyoma...
January 1, 2017: Reproductive Sciences
https://www.readbyqxmd.com/read/28107834/a-label-free-colorimetric-isothermal-cascade-amplification-for-the-detection-of-disease-related-nucleic-acids-based-on-double-hairpin-molecular-beacon
#13
Dong Wu, Huo Xu, Haimei Shi, Weihong Li, Mengze Sun, Zai-Sheng Wu
K-Ras mutations at codon 12 play an important role in an early step of carcinogenesis. Here, a label-free colorimetric isothermal cascade amplification for ultrasensitive and specific detection of K-Ras point mutation is developed based on a double-hairpin molecular beacon (DHMB). The biosensor consists of DHMB probe and a primer-incorporated polymerization template (PPT) designed partly complementary to DHMB. In the presence of polymerase, target DNA is designed to trigger strand displacement amplification (SDA) via promote the hybridization of PPT with DHMB and subsequently initiates cascade amplification process with the help of the nicking endonuclease...
March 8, 2017: Analytica Chimica Acta
https://www.readbyqxmd.com/read/28106537/down-regulation-of-pseudogene-vimentin-2p-is-associated-with-poor-outcome-in-de-novo-acute-myeloid-leukemia
#14
Ling-Ling Zhai, Jiao Zhou, Jing Zhang, Xi Tang, Ling-Yu Zhou, Jia-Yu Yin, Minse-Evola Deniz Vanessa, Wen Peng, Jiang Lin, Zhao-Qun Deng
OBJECTIVES: This study was intended to investigate the expression status of Vimentin 2p (VIM 2p), a pseudogene of Vimentin, and further analyze its clinical significance in AML patients. METHODS: Real-time quantitative PCR (RQ-PCR) was employed to explore the expression status of VIM 2p in 128 patients with de novo AML and 36 healthy controls. RESULTS: The expression level of VIM 2p was significantly decreased compared with healthy controls (P< 0...
January 13, 2017: Cancer Biomarkers: Section A of Disease Markers
https://www.readbyqxmd.com/read/28105192/akt-dependent-activation-of-erk-by-cyclin-d1b-contributes-to-cell-invasiveness-and-tumorigenicity
#15
Chul Jang Kim, Yukihiro Tambe, Ken-Ichi Mukaisho, Hiroyuki Sugihara, Akihiro Kawauchi, Hirokazu Inoue
A total of two major isoforms, cyclin D1a and cyclin D1b, are generated from the human cyclin D1 gene by alternative splicing. Cyclin D1b is scarcely expressed in normal tissues; however, it is expressed at a high frequency in certain types of cancerous tissue. The present authors previously constructed cyclin D1b transgenic (Tg) mice and identified rectal tumors, including adenocarcinoma and sessile serrated adenoma, in 62.5% of female Tg mice. In addition, the present authors indicated that cyclin D1b expression enhances phosphorylation of extracellular signal-regulated kinase (Erk) in these rectal tumors, and in mouse embryonic fibroblast (MEF) cells and human 293T cells...
December 2016: Oncology Letters
https://www.readbyqxmd.com/read/28104492/constitutively-active-ras-signaling-reduces-1-25-dihydroxyvitamin-d-mediated-gene-transcription-in-intestinal-epithelial-cells-by-reducing-vitamin-d-receptor-expression
#16
REVIEW
Marsha L DeSmet, James C Fleet
High vitamin D status is associated with reduced colon cancer risk but these studies ignore the diversity in the molecular etiology of colon cancer. RAS activating mutations are common in colon cancer and they activate pro-proliferative signaling pathways. We examined the impact of RAS activating mutations on 1,25 dihydroxyvitamin D (1,25(OH)2D)-mediated gene expression in cultured colon and intestinal cell lines. Transient transfection of Caco-2 cells with a constitutively active mutant K-RAS (G12 V) significantly reduced 1,25(OH)2D-induced activity of both a human 25-hydroxyvitamin D, 24 hydroxyase (CYP24A1) promoter-luciferase and an artificial 3X vitamin D response element (VDRE) promoter-luciferase reporter gene...
January 16, 2017: Journal of Steroid Biochemistry and Molecular Biology
https://www.readbyqxmd.com/read/28102292/integrated-molecular-analysis-reveals-complex-interactions-between-genomic-and-epigenomic-alterations-in-esophageal-adenocarcinomas
#17
DunFa Peng, Yan Guo, Heidi Chen, Shilin Zhao, Kay Washington, TianLing Hu, Yu Shyr, Wael El-Rifai
The incidence of esophageal adenocarcinoma (EAC) is rapidly rising in the United States and Western countries. In this study, we carried out an integrative molecular analysis to identify interactions between genomic and epigenomic alterations in regulating gene expression networks in EAC. We detected significant alterations in DNA copy numbers (CN), gene expression levels, and DNA methylation profiles. The integrative analysis demonstrated that altered expression of 1,755 genes was associated with changes in CN or methylation...
January 19, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28093501/discrete-cytosolic-macromolecular-braf-complexes-exhibit-distinct-activities-and-composition
#18
Britta Diedrich, Kristoffer Tg Rigbolt, Michael Röring, Ricarda Herr, Stephanie Kaeser-Pebernard, Christine Gretzmeier, Robert F Murphy, Tilman Brummer, Jörn Dengjel
As a central element within the RAS/ERK pathway, the serine/threonine kinase BRAF plays a key role in development and homeostasis and represents the most frequently mutated kinase in tumors. Consequently, it has emerged as an important therapeutic target in various malignancies. Nevertheless, the BRAF activation cycle still raises many mechanistic questions as illustrated by the paradoxical action and side effects of RAF inhibitors. By applying SEC-PCP-SILAC, we analyzed protein-protein interactions of hyperactive BRAF(V)(600E) and wild-type BRAF (BRAF(WT))...
January 16, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28088467/stat3-signaling-mediates-tumour-resistance-to-egfr-targeted-therapeutics
#19
Ahmad A Zulkifli, Fiona H Tan, Tracy L Putoczki, Stanley S Stylli, Rodney B Luwor
Several EGFR inhibitors are currently undergoing clinical assessment or are approved for the clinical management of patients with varying tumour types. However, treatment often results in a lack of response in many patients. The majority of patients that initially respond eventually present with tumours that display acquired resistance to the original therapy. A large number of receptor tyrosine and intracellular kinases have been implicated in driving signaling that mediates this tumour resistance to anti-EGFR targeted therapy, and in a few cases these discoveries have led to overall changes in prospective tumour screening and clinical practice (K-RAS in mCRC and EGFR T790M in NSCLC)...
January 11, 2017: Molecular and Cellular Endocrinology
https://www.readbyqxmd.com/read/28079954/conformational-sers-classification-of-k-ras-point-mutations-for-cancer-diagnostics
#20
Judit Morla-Folch, Patricia Gisbert-Quilis, Matteo Masetti, Eduardo Garcia-Rico, Ramon A Alvarez-Puebla, Luca Guerrini
Point mutations in Ras oncogenes are routinely screened for diagnostics and treatment of tumors (especially in colorectal cancer). Here, we develop an optical approach based on direct SERS coupled with chemometrics for the study of the specific conformations that single-point mutations impose on a relatively large fragment of the K-Ras gene (141 nucleobases). Results obtained offer the unambiguous classification of different mutations providing a potentially useful insight for diagnostics and treatment of cancer in a sensitive, fast, direct and inexpensive manner...
January 12, 2017: Angewandte Chemie
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