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https://www.readbyqxmd.com/read/27936442/label-free-colorimetric-detection-of-cancer-related-gene-based-on-two-step-amplification-of-molecular-machine
#1
Huo Xu, Dong Wu, Chen-Qiao Li, Zheng Lu, Xiao-Yun Liao, Jie Huang, Zai-Sheng Wu
Highly sensitive detection of K-ras gene is of great significance in biomedical research and clinical diagnosis. Here, we developed a colorimetric biosensing system for the detection of proto-oncogene K-ras based on enhanced amplification effect of DNA molecular machine, where dual isothermal circular strand-displacement amplification (D-SDA) occurs on two arms in one-to-one correspondence. Specifically, we designed a primer-locked hairpin probe (HP) and a primer-contained linear polymerization template (PPT)...
December 2, 2016: Biosensors & Bioelectronics
https://www.readbyqxmd.com/read/27925213/the-p53-inhibitor-mdm4-cooperates-with-multiple-genetic-lesions-in-tumorigenesis
#2
Shunbin Xiong, Vinod Pant, Yun Zhang, Neeraj K Aryal, M James You, Donna Kusewitt, Guillermina Lozano
The p53 inhibitor Mdm4 is present at high levels in multiple human cancers. Overexpression of Mdm4 in mice drives spontaneous development of mostly lymphomas and sarcomas. In this study, we explored the ability of Mdm4 to cooperate with other lesions in tumour development. The Mdm4 transgene contributed to mammary tumour development in a BALB/cJ background. High levels of Mdm4 enhanced tumour development in a mutant p53R172H heterozygous background and reduced the need to lose the wild type p53 allele as compared to the mice heterozygous only for the p53R172H mutation...
December 7, 2016: Journal of Pathology
https://www.readbyqxmd.com/read/27924574/genetic-validation-of-cell-proliferation-via-ras-independent-activation-of-the-raf-mek-erk-pathway
#3
Carmen G Lechuga, Lucía Simón-Carrasco, Harrys K C Jacob, Matthias Drosten
Signaling transmitted by the Ras family of small GTPases (H-, N-, and K-Ras) is essential for proliferation of mouse embryonic fibroblasts (MEFs). However, constitutive activation of the downstream Raf/Mek/Erk pathway can bypass the requirement for Ras proteins and allow cells to proliferate in the absence of the three Ras isoforms. Here we describe a protocol for a colony formation assay that permits evaluating the role of candidate proteins that are positive or negative regulators of cell proliferation mediated via Ras-independent Raf/Mek/Erk pathway activation...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/27911813/spatiotemporal-imaging-of-small-gtpases-activity-in-live-cells
#4
Stephanie Voss, Dennis M Krüger, Oliver Koch, Yao-Wen Wu
Ras-like small GTPases function as molecular switches and regulate diverse cellular events. To examine the dynamics of signaling requires spatiotemporal visualization of their activity in the cell. Current small GTPase sensors rely on specific effector domains that are available for only a small number of GTPases and compete for endogenous regulator/effector binding. Here, we describe versatile conformational sensors for GTPase activity (COSGAs) based on the conserved GTPase fold. Conformational changes upon GDP/GTP exchange were directly observed in solution, on beads, and in live cells by Förster resonance energy transfer (FRET)...
November 29, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27910065/pathology-of-endometrial-carcinoma
#5
Sigurd F Lax
On a clinicopathological and molecular level, two distinctive types of endometrial carcinoma, type I and type II, can be distinguished. Endometrioid carcinoma, the typical type I carcinoma, seems to develop through an estrogen-driven "adenoma carcinoma" pathway from atypical endometrial hyperplasia/endometrioid intraepithelial neoplasia (AEH/EIN). It is associated with elevated serum estrogen and high body mass index and expresses estrogen and progesterone receptors. They are mostly low grade and show a favorable prognosis...
2017: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/27909058/secreted-glioblastoma-nanovesicles-contain-intracellular-signaling-proteins-and-active-ras-incorporated-in-a-farnesylation-dependent-manner
#6
Natalie Luhtala, Aaron Aslanian, John R Yates, Tony Hunter
Glioblastomas (GBMs) are malignant brain tumors with a median survival of less than 18 months. Redundancy of signaling pathways represented within GBMs contributes to their therapeutic resistance. Exosomes are extracellular nanovesicles released from cells and present in human biofluids that represent a possible biomarker of tumor signaling state that could aid in personalized treatment. Herein, we demonstrate that mouse GBM cell-derived extracellular nanovesicles resembling exosomes from an H-RasV12 myr-Akt mouse model for GBM are enriched for intracellular signaling cascade proteins (GO: 0007242) and Ras protein signal transduction (GO: 0007265), and contain active Ras...
December 1, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27904769/disruption-of-actin-filaments-and-suppression-of-pancreatic-cancer-cell-viability-and-migration-following-treatment-with-polyisoprenylated-cysteinyl-amides
#7
Augustine T Nkembo, Olufisayo Salako, Rosemary A Poku, Felix Amissah, Elizabeth Ntantie, Hernan Flores-Rozas, Nazarius S Lamango
Pancreatic cancer is characterized by K-Ras mutations in over 90% of the cases. The mutations make the tumors aggressive and resistant to current therapies resulting in very poor prognoses. Valiant efforts to drug mutant K-Ras and related proteins for the treatment of cancers with Ras mutations have been elusive. The need thus persists for therapies to target and suppress the hyperactive K-Ras mutant proteins to normal levels of activity. Polyisoprenylated cysteinyl amide inhibitors (PCAIs) of polyisoprenylated methylated protein methyl esterase (PMPMEase) were designed to disrupt polyisoprenylated protein metabolism and/or functions...
2016: American Journal of Cancer Research
https://www.readbyqxmd.com/read/27895786/sprouty4-mrna-variants-and-protein-expressions-in-breast-and-lung-derived-cells
#8
Angelina Doriguzzi, Jihen Salhi, Hedwig Sutterlüty-Fall
Sprouty proteins are modulators of mitogen-induced signalling processes and are therefore hypothesized to affect malignant diseases. As a member of the Sprouty family, Sprouty4 has been previously shown to function as a tumour suppressor in lung and breast cancer. The present study analysed the expression of two known Sprouty4 splice variants in cells established from malignant and normal lung and breast tissues using semi-quantitative reverse transcription-polymerase chain reaction and immunoblotting. The results indicated that the expression of the two messenger RNA (mRNA) variants was reduced in the cells derived from malignant tissue in comparison to the normal counterparts...
November 2016: Oncology Letters
https://www.readbyqxmd.com/read/27880995/frequency-of-k-ras-and-n-ras-gene-mutations-in-colorectal-cancers-in-southeastern-iran
#9
Naseri Mohsen, Sebzari Ahmadreza, Haghighi Fatemeh, Hajipoor Fatemeh, Emadian Razavi Fariba
Background: K-RAS and N-RAS gene mutations cause resistance to treatment in patients with colorectal cancer. Based on this, awareness of mutation of these genes is considered a clinically important step towards better diagnosis and appropriate treatment. Materials and Methods: Fifty paraffin-embedded blocks of colorectal cancer were obtained from Imam Reza Hospital of Birjand, Iran. Following DNA extraction, the samples were analyzed for common mutations of exons 2, 3 and 4 of KRAS and NRAS genes using real time PCR and pyrosequencing...
January 9, 2016: Asian Pacific Journal of Cancer Prevention: APJCP
https://www.readbyqxmd.com/read/27880935/evolutionary-biologic-changes-of-gut-microbiota-in-an-adenoma-carcinoma-sequence-mouse-colorectal-cancer-model-induced-by-1-2-dimethylhydrazine
#10
Teng Sun, Shanglong Liu, Yanbing Zhou, Zengwu Yao, Dongfeng Zhang, Shougen Cao, Zhiliang Wei, Bin Tan, Yi Li, Zheng Lian, Song Wang
The molecular biological mechanisms underlying the evolutionary biologic changes leading to carcinogenesis remain unclear. The main objective of our study was to explore the evolution of the microbiota community and molecules related with CRC in the dynamic transition from normal colon epithelium to premalignant adenoma with the aid of an 'adenoma-carcinoma sequence' mouse CRC model induced by DMH. We generated a modified mouse CRC model induced by DMH for DNA sequences, and characterized the molecular networks...
November 18, 2016: Oncotarget
https://www.readbyqxmd.com/read/27873522/extremely-well-differentiated-papillary-thyroid-carcinoma-resembling-adenomatous-hyperplasia-can-metastasize-to-the-skull-a-case-report
#11
Ju Yeon Pyo, Jisup Kim, Sung Eun Choi, Eunah Shin, Seok Woo Yang, Cheong Soo Park, Seok Mo Kim, Soonwon Hong
We describe herein histologic, immunohistochemical, and molecular findings and clinical manifestations of a rare case of an extremely well differentiated papillary thyroid carcinoma (EWD-PTC). Similarly, it is also difficult to diagnose follicular variant papillary thyroid carcinoma (FVPTC), whose diagnosis is still met with controversy. A recently reported entity of well-differentiated tumor of uncertain malignant potential (WDT-UMP) is added to the diagnostic spectrum harboring EWD-PTC and FVPTC. We report this case, because EWD-PTC is different from FVPTC in its papillary architecture, and also from WDT-UMP in its recurrence and metastatic pattern...
January 2017: Yonsei Medical Journal
https://www.readbyqxmd.com/read/27872088/h-ras-and-k-ras-oncoproteins-induce-different-tumor-spectra-when-driven-by-the-same-regulatory-sequences
#12
Matthias Drosten, Lucía Simón-Carrasco, Isabel Hernández-Porras, Carmen G Lechuga, María T Blasco, Harrys Kc Jacob, Salvatore Fabbiano, Nicoletta Potenza, Xosé R Bustelo, Carmen Guerra, Mariano Barbacid
Genetic studies in mice have provided evidence that H-Ras and K-Ras proteins are bioequivalent. However, human tumors display marked differences in the association of RAS oncogenes with tumor type. Thus, to further assess the bioequivalency of oncogenic H-Ras and K-Ras, we replaced the coding region of the murine K-Ras locus with H-RasG12V oncogene sequences. Germline expression of H-RasG12V or K-RasG12V from the K-Ras locus resulted in embryonic lethality. However, expression of these genes in adult mice led to different tumor phenotypes...
November 21, 2016: Cancer Research
https://www.readbyqxmd.com/read/27865780/rasins-genetically-encoded-intrabodies-of-activated-ras-proteins
#13
Mehmet Cetin, William E Evenson, Garret G Gross, Farzad Jalali-Yazdi, Daniel Krieger, Don Arnold, Terry T Takahashi, Richard W Roberts
K- and H-Ras are the most commonly mutated genes in human tumors and are critical for conferring and maintaining the oncogenic phenotype in tumors with poor prognoses. Here, we design genetically encoded antibody-like ligands (intrabodies) that recognize active, GTP-bound K- and H-Ras. These ligands, which use the 10th domain of human fibronectin as their scaffold, are stable inside cells and when fused with a fluorescent protein label constitutively active G12V mutant H-Ras. Primary selection of ligands against Ras with mRNA display resulted in an intrabody (termed RasIn1) that binds with a KD of 2...
November 16, 2016: Journal of Molecular Biology
https://www.readbyqxmd.com/read/27863786/preoperative-detection-of-ras-mutation-may-guide-extent-of-thyroidectomy
#14
Snehal G Patel, Sally E Carty, Kelly L McCoy, N Paul Ohori, Shane O LeBeau, Raja R Seethala, Marina N Nikiforova, Yuri E Nikiforov, Linwah Yip
BACKGROUND: Preoperative detection of RAS mutations can contribute to cancer risk assessment in indeterminate thyroid nodules, although RAS is not always associated with malignancy. METHODS: Fine-needle aspiration samples classified in 1 of 3 indeterminate cytology categories were prospectively tested for N-, H-, and K-RAS mutations using next-generation sequencing assay. RESULTS: In the study, 93 patients with 94 nodules had preoperative RAS detected, of whom 86 patients had an operation (69% total thyroidectomy, 29% lobectomy)...
November 15, 2016: Surgery
https://www.readbyqxmd.com/read/27853654/tumor-necrosis-factor-links-chronic-obstructive-pulmonary-disease-and-k-ras-mutant-lung-cancer-through-induction-of-an-immunosuppressive-pro-tumor-microenvironment
#15
Lei Gong, Mauricio da Silva Caetano, Amber M Cumpian, Soudabeh Daliri, Alejandra Garza Flores, Seon Hee Chang, Cesar E Ochoa, Christopher M Evans, Zhentao Yu, Seyed Javad Moghaddam
Tumor necrosis factor (TNF) is known as an important regulator of tumor microenvironment and inflammation. TNF levels are markedly elevated in the bronchoalveolar lavage fluid (BALF) of patients with chronic obstructive pulmonary disease (COPD), which is an independent risk factor for lung cancer. We have previously shown that COPD-like airway inflammation promotes lung cancer in a K-ras mutant mouse model (CC-LR mouse). This was associated with a significant increase of neutrophils in BALF, accompanied by a marked increase in TNF level, suggesting a link between COPD, TNF, and lung cancer promotion...
2016: Oncoimmunology
https://www.readbyqxmd.com/read/27845397/intrinsic-k-ras-dynamics-a-novel-molecular-dynamics-data-analysis-method-shows-causality-between-residue-pair-motions
#16
Sezen Vatansever, Zeynep H Gümüş, Burak Erman
K-Ras is the most frequently mutated oncogene in human cancers, but there are still no drugs that directly target it in the clinic. Recent studies utilizing dynamics information show promising results for selectively targeting mutant K-Ras. However, despite extensive characterization, the mechanisms by which K-Ras residue fluctuations transfer allosteric regulatory information remain unknown. Understanding the direction of information flow can provide new mechanistic insights for K-Ras targeting. Here, we present a novel approach -conditional time-delayed correlations (CTC) - using the motions of all residue pairs of a protein to predict directionality in the allosteric regulation of the protein fluctuations...
November 15, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27835580/ky1022-a-small-molecule-destabilizing-ras-via-targeting-the-wnt-%C3%AE-catenin-pathway-inhibits-development-of-metastatic-colorectal-cancer
#17
Yong-Hee Cho, Pu-Hyeon Cha, Saluja Kaduwal, Jong-Chan Park, Sang-Kyu Lee, Jeong-Soo Yoon, Wookjin Shin, Hyuntae Kim, Eun Ji Ro, Kyung-Hwa Koo, Ki-Sook Park, Gyoonhee Han, Kang-Yell Choi
APC (80-90%) and K-Ras (40-50%) mutations frequently occur in human colorectal cancer (CRC) and these mutations cooperatively accelerate tumorigenesis including metastasis. In addition, both β-catenin and Ras levels are highly increased in CRC, especially in metastatic CRC (mCRC). Therefore, targeting both the Wnt/β-catenin and Ras pathways could be an ideal therapeutic approach for treating mCRC patients. In this study, we characterized the roles of KY1022, a small molecule that destabilizes both β-catenin and Ras via targeting the Wnt/β-catenin pathway, in inhibiting the cellular events, including EMT, an initial process of metastasis, and apoptosis...
November 7, 2016: Oncotarget
https://www.readbyqxmd.com/read/27834959/k-ras-oncogene-mutation-in-pterygium
#18
B T Ozturk, M S Yıldırım, A Zamani, B Bozkurt
PurposePterygium is claimed to be a benign proliferation triggered by prolonged exposure to ultraviolet radiation. The frequency of K-ras oncogene mutation, which is among the initial mutations in tumorigenesis, is evaluated in this study.Patients and methodsIn this prospective randomized clinical, trial pterygium tissues and normal conjunctiva tissue specimens are obtained from the superotemporal quadrant of patients who underwent primary pterygium excision with autograft transplantation. DNA extraction from tissues was performed using the QIAamp DNA FFPE tissue kit...
November 11, 2016: Eye
https://www.readbyqxmd.com/read/27820802/inhibition-of-ras-function-through-targeting-an-allosteric-regulatory-site
#19
Russell Spencer-Smith, Akiko Koide, Yong Zhou, Raphael R Eguchi, Fern Sha, Priyanka Gajwani, Dianicha Santana, Ankit Gupta, Miranda Jacobs, Erika Herrero-Garcia, Jacqueline Cobbert, Hugo Lavoie, Matthew Smith, Thanashan Rajakulendran, Evan Dowdell, Mustafa Nazir Okur, Irina Dementieva, Frank Sicheri, Marc Therrien, John F Hancock, Mitsuhiko Ikura, Shohei Koide, John P O'Bryan
RAS GTPases are important mediators of oncogenesis in humans. However, pharmacological inhibition of RAS has proved challenging. Here we describe a functionally critical region, located outside the effector lobe of RAS, that can be targeted for inhibition. We developed NS1, a synthetic binding protein (monobody) that bound with high affinity to both GTP- and GDP-bound states of H-RAS and K-RAS but not N-RAS. NS1 potently inhibited growth factor signaling and oncogenic H-RAS- and K-RAS-mediated signaling and transformation but did not block oncogenic N-RAS, BRAF or MEK1...
November 7, 2016: Nature Chemical Biology
https://www.readbyqxmd.com/read/27809361/development-of-pyridazinone-chemotypes-targeting-the-pde%C3%AE-prenyl-binding-site
#20
Sandip Murarka, Pablo Martín-Gago, Carsten Schultz-Fademrecht, Alaa Al Saabi, Matthias Baumann, Eyad Fansa, Shehab Ismail, Peter Nussbaumer, Alfred Wittinghofer, Herbert Waldmann
The K-Ras GTPase is a major target in anticancer drug discovery. However, direct interference with signaling by K-Ras has not led to clinically useful drugs yet. Correct localization and signaling by farnesylated K-Ras is regulated by the prenyl binding protein PDEδ. Interfering with binding of PDEδ to K-Ras by means of small molecules provides a novel opportunity to suppress oncogenic signaling. Here we describe the identification and structure-guided development of novel K-Ras-PDEδ inhibitor chemotypes based on pyrrolopyridazinones and pyrazolopyridazinones that bind to the farnesyl binding pocket of PDEδ with low nanomolar affinity...
November 3, 2016: Chemistry: a European Journal
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