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https://www.readbyqxmd.com/read/27913578/characterization-of-egfr-t790m-l792f-and-c797s-mutations-as-mechanisms-of-acquired-resistance-to-afatinib-in-lung-cancer
#1
Yoshihisa Kobayashi, Koichi Azuma, Hiroki Nagai, Young Hak Kim, Yosuke Togashi, Yuichi Sesumi, Masato Chiba, Masaki Shimoji, Katsuaki Sato, Kenji Tomizawa, Toshiki Takemoto, Kazuto Nishio, Tetsuya Mitsudomi
Lung cancers harboring common EGFR mutations respond to EGFR tyrosine kinase inhibitors (TKIs). We previously reported that tumors with exon 18 mutations are particularly sensitive to irreversible second-generation (2G) afatinib compared with 1G-TKIs. However, data on the mechanisms of acquired resistance to afatinib are limited. We established afatinib-resistant cells by transfecting Ba/F3 cells with common or exon 18 (G719A and Del18) mutations and subjecting them to chronic exposure to increasing concentrations of afatinib...
December 2, 2016: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/27907103/tbx20-is-an-essential-regulator-of-embryonic-heart-growth-in-zebrafish
#2
Steffen Just, Linda Raphel, Ina M Berger, Anja Bühler, Mirjam Keßler, Wolfgang Rottbauer
The molecular mechanisms that regulate cardiomyocyte proliferation during embryonic heart growth are not completely deciphered yet. In a forward genetic N-ethyl-N-nitrosourea (ENU) mutagenesis screen, we identified the recessive embryonic-lethal zebrafish mutant line weiches herz (whz). Homozygous mutant whz embryos display impaired heart growth due to diminished embryonic cardiomyocyte proliferation resulting in cardiac hypoplasia and weak cardiac contraction. By positional cloning, we found in whz mutant zebrafish a missense mutation within the T-box 20 (Tbx20) transcription factor gene leading to destabilization of Tbx20 protein...
2016: PloS One
https://www.readbyqxmd.com/read/27884590/physical-activity-induced-protection-against-breast-cancer-risk-associated-with-delayed-parity
#3
Kathleen M Sturgeon, Aaron Schweitzer, John J Leonard, Deirdre K Tobias, Ying Liu, Elizabeth Cespedes Feliciano, Vasanti S Malik, Amit Joshi, Bernard Rosner, Bart C De Jonghe
Epidemiological evidence indicates that physical activity between menarche and first pregnancy is associated with a lower risk of breast cancer among women with at least 20years between these reproductive events. The mechanism by which physical activity during this interval confers protection is unknown. This study used a novel animal model to assess potentially protective effects of physical activity on tumor development in delayed parity. Thirty-six female Sprague Dawley rats received an i.p. injection of 50mg/kg N-methyl-N-nitrosourea (MNU) at 5weeks of age...
November 21, 2016: Physiology & Behavior
https://www.readbyqxmd.com/read/27880821/inhibition-of-the-tgf%C3%AE-pathway-enhances-retinal-regeneration-in-adult-zebrafish
#4
Christoph Tappeiner, Ellinor Maurer, Pauline Sallin, Thomas Bise, Volker Enzmann, Markus Tschopp
In contrast to the mammalian retina, the zebrafish retina exhibits the potential for lifelong retinal neurogenesis and regeneration even after severe damage. Previous studies have shown that the transforming growth factor beta (TGFβ) signaling pathway is activated during the regeneration of different tissues in the zebrafish and is needed for regeneration in the heart and the fin. In this study, we have investigated the role of the TGFβ pathway in the N-methyl-N-nitrosourea (MNU)-induced chemical model of rod photoreceptor de- and regeneration in adult zebrafish...
2016: PloS One
https://www.readbyqxmd.com/read/27866331/photoreceptor-degeneration-by-intravitreal-injection-of-n-methyl-n-nitrosourea-mnu-in-rabbits-a-pilot-study
#5
Sarah Rösch, Claudia Werner, Frank Müller, Peter Walter
BACKGROUND: Pilot study on the attempt to induce selective photoreceptor degeneration in the rabbit eye by intravitreal injection of MNU, facing the difficulties of the evaluation of retinal degeneration by different in-vivo and in-vitro methods in such a large eye animal model. METHODS: Eight pigmented Chinchilla Bastard rabbits were injected intravitreally with MNU (1 × 1mg/kg body weight (BW), 1 × 2mg/kg BW, 3 × 3mg/kg BW, 1 × 4mg/kg BW, 1 × 6mg/kg BW, and 1 × DMSO + PBS as control)...
November 19, 2016: Graefe's Archive for Clinical and Experimental Ophthalmology
https://www.readbyqxmd.com/read/27862073/n-methyl-n-nitrosourea-induces-retinal-degeneration-in-the-rat-via-the-inhibition-of-nf-%C3%AE%C2%BAb-activation
#6
Yu Xiong, Hong-Pei Ji, Wei-Tao Song, Ye-Wei Yin, Chao-Hua Xia, Bei Xu, Yi Xu, Xiao-Bo Xia
Retinitis pigmentosa (RP) is a group of inherited neurodegenerative diseases characterized by the loss of photoreceptor cells through apoptosis. N-methyl-N-nitrosourea (MNU) is an alkylating toxicant that induces photoreceptor cell death resembling hereditary RP. This study aimed to investigate the role of nuclear factor κB (NF-κB) in MNU-induced photoreceptor degeneration. Adult rats received a single intraperitoneal injection of MNU (60 mg/kg bodyweight). Hematoxylin and eosin staining demonstrated progressive outer nuclear layer (ONL) loss after MNU treatment...
November 13, 2016: Cell Biochemistry and Function
https://www.readbyqxmd.com/read/27848995/a-novel-enu-induced-ankyrin-1-mutation-impairs-parasite-invasion-and-increases-erythrocyte-clearance-during-malaria-infection-in-mice
#7
Hong Ming Huang, Denis C Bauer, Patrick M Lelliott, Andreas Greth, Brendan J McMorran, Simon J Foote, Gaetan Burgio
Genetic defects in various red blood cell (RBC) cytoskeletal proteins have been long associated with changes in susceptibility towards malaria infection. In particular, while ankyrin (Ank-1) mutations account for approximately 50% of hereditary spherocytosis (HS) cases, an association with malaria is not well-established, and conflicting evidence has been reported. We describe a novel N-ethyl-N-nitrosourea (ENU)-induced ankyrin mutation MRI61689 that gives rise to two different ankyrin transcripts: one with an introduced splice acceptor site resulting a frameshift, the other with a skipped exon...
November 16, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27815463/effects-of-dietary-xanthophylls-canthaxanthin-and-astaxanthin-on-n-methyl-n-nitrosourea-induced-rat-mammary-carcinogenesis
#8
Takashi Yuri, Katsuhiko Yoshizawa, Yuko Emoto, Yuichi Kinoshita, Michiko Yuki, Airo Tsubura
BACKGROUND: Natural xanthophylls, canthaxanthin and astaxanthin are known to exhibit anticancer activity. However, the dietary effects of canthaxanthin and astaxanthin on N-methyl-N-nitrosourea (MNU)-induced mammary cancer remain controversial, and their mechanisms of action have not been clearly identified. MATERIALS AND METHODS: Three-week-old female Sprague-Dawley rats were fed a xanthophyll-free (basal diet) diet or experimental diets containing canthaxanthin or astaxanthin (0...
November 2016: In Vivo
https://www.readbyqxmd.com/read/27809286/the-development-of-a-parenteral-pharmaceutical-formulation-of-a-new-class-of-compounds-of-nitrosourea
#9
Ludmila Nikolaeva, Natalia Oborotova, Natalia Bunyatyan, Xi Zhang, Ekaterina Sanarova, Anna Lantsova, Olga Orlova, Alevtina Polozkova
Despite the rapid development of medical technologies, chemotherapy treatment still occupies an important place in clinical oncology. In this regard, the current research in this area focuses on the synthesis of new highly effective antitumor substances that have minimal side effects and the development of stable pharmaceutical formulations (PF) on their basis. In order to solve this problem, the I. Ya. Postovsky Institute of Organic Synthesis of the Ural Branch of the Russian Academy of Sciences actively sought for original substances, namely, nitrosourea (NU) derivatives, one of the most promising classes of anticancer drugs...
November 1, 2016: Pharmaceuticals
https://www.readbyqxmd.com/read/27795689/identification-and-linkage-analysis-of-a-new-rice-bacterial-blight-resistance-gene-from-xm14-a-mutant-line-from-ir24
#10
Constantine Busungu, Satoru Taura, Jun-Ichi Sakagami, Katsuyuki Ichitani
Bacterial blight caused by Xanthomonas oryzae pv. oryzae (Xoo) is a chief factor limiting rice productivity worldwide. XM14, a rice mutant line resistant to Xoo, has been obtained by treating IR24, which is susceptible to six Philippine Xoo races and six Japanese Xoo races, with N-methyl-N-nitrosourea. XM14 showed resistance to six Japanese Xoo races. The F2 population from XM14 × IR24 clearly showed 1 resistant : 3 susceptible segregation, suggesting control of resistance by a recessive gene. The approximate chromosomal location of the resistance gene was determined using 10 plants with shortest lesion length in the F2 population from XM14 × Koshihikari, which is susceptible to Japanese Xoo races...
September 2016: Breeding Science
https://www.readbyqxmd.com/read/27777124/effect-of-pharmacologically-induced-retinal-degeneration-on-retinal-autofluorescence-lifetimes-in-mice
#11
Chantal Dysli, Muriel Dysli, Martin S Zinkernagel, Volker Enzmann
Fluorescence lifetime imaging ophthalmoscopy (FLIO) was used to investigate retinal autofluorescence lifetimes in mouse models of pharmacologically induced retinal degeneration over time. Sodium iodate (NaIO3, 35 mg/kg intravenously) was used to induce retinal pigment epithelium (RPE) degeneration with subsequent loss of photoreceptors (PR) whereas N-methyl-N-nitrosourea (MNU, 45 mg/kg intraperitoneally) was employed for degeneration of the photoreceptor cell layer alone. All mice were measured at day 3, 7, 14, and 28 after the respective injection of NaIO3, MNU or NaCl (control)...
October 21, 2016: Experimental Eye Research
https://www.readbyqxmd.com/read/27776689/dose-dependent-de-novo-germline-mutations-detected-by-whole-exome-sequencing-in-progeny-of-enu-treated-male-gpt-delta-mice
#12
Kenichi Masumura, Naomi Toyoda-Hokaiwado, Akiko Ukai, Yoichi Gondo, Masamitsu Honma, Takehiko Nohmi
Germline mutations are an important component of genetic toxicology; however, mutagenicity tests of germline cells are limited. Recent advances in sequencing technology can be used to detect mutations by direct sequencing of genomic DNA (gDNA). We previously reported induced de novo mutations detected using whole-exome sequencing in the offspring of N-ethyl-N-nitrosourea (ENU)-treated mice in a single-dose experiment (85mg/kg, i.p., weekly on two occasions). In this study, two lower doses (10 and 30mg/kg) were added, and dose-response of inherited germline mutations was analyzed...
November 1, 2016: Mutation Research
https://www.readbyqxmd.com/read/27772925/inhibitory-effects-of-malaysian-tualang-honey-and-australian-new-zealand-manuka-honey-in-modulating-experimental-breast-cancers-induced-by-n-methyl-n-nitrosourea-mnu-a-comparative-study
#13
Nor Hayati Othman, Sarfraz Ahmed, Siti Amrah Sulaiman
No abstract text is available yet for this article.
February 2016: Pathology
https://www.readbyqxmd.com/read/27770464/in-vivo-pig-a-gene-mutation-assay-guidance-for-3rs-friendly-implementation
#14
Marian Raschke, Bernd-W Igl, Julia Kenny, Joanne Collins, Stephen D Dertinger, Carson Labash, Javed A Bhalli, Cameron C M Tebbe, Kylie M McNeil, Andreas Sutter
The rodent Pig-a assay is an in vivo method for the detection of gene mutation, where lack of glycosylphosphatidylinositol-anchored proteins on the surface of circulating red blood cells (RBCs) serves as a reporter for Pig-a gene mutation. In the case of rats, the frequency of mutant phenotype RBCs is measured via fluorescent anti-CD59 antibodies and flow cytometry. The Pig-a assay meets the growing expectations for novel approaches in animal experimentation not only focusing on the scientific value of the assay but also on animal welfare aspects (3Rs principles), for example, amenable to integration into pivotal rodent 28-day general toxicology studies...
December 2016: Environmental and Molecular Mutagenesis
https://www.readbyqxmd.com/read/27758718/current-and-future-drug-treatments-for-glioblastomas
#15
Shigeo Ohba, Yuichi Hirose
Glioblastomas are the most aggressive of all gliomas and have the worst prognosis, with 5-year survival rates of less than 10%. Temozolomide (TMZ) is a DNA-methylating agent. Now that TMZ is available, the standard treatment is to resect as much of the tumor as possible without inducing unacceptable neurologic deficits, followed by treatment with radiation and TMZ. TMZ has also been used for maintenance therapy. Recently, bevacizumab, which is a monoclonal antibody to vascular endothelial growth factor, has been used for the initial treatment of glioblastomas and for the treatment of recurrent glioblastomas...
October 14, 2016: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/27739633/diet-induced-obesity-increases-the-frequency-of-pig-a-mutant-erythrocytes-in-male-c57bl-6j-mice
#16
Jeffrey K Wickliffe, Stephen D Dertinger, Dorothea K Torous, Svetlana L Avlasevich, Bridget R Simon-Friedt, Mark J Wilson
Obesity increases the risk of a number of chronic diseases in humans including several cancers. Biological mechanisms responsible for such increased risks are not well understood at present. Increases in systemic inflammation and oxidative stress, endogenous production of mutagenic metabolites, altered signaling in proliferative pathways, and increased sensitivity to exogenous mutagens and carcinogens are some of the potential contributing factors. We hypothesize that obesity creates an endogenously mutagenic environment in addition to increasing the sensitivity to environmental mutagens...
December 2016: Environmental and Molecular Mutagenesis
https://www.readbyqxmd.com/read/27738081/analysis-of-genes-involved-in-the-pi3k-akt-pathway-in-radiation-and-mnu-induced-rat-mammary-carcinomas
#17
Kaye Showler, Mayumi Nishimura, Kazuhiro Daino, Tatsuhiko Imaoka, Yukiko Nishimura, Takamitsu Morioka, Benjamin J Blyth, Toshiaki Kokubo, Masaru Takabatake, Maki Fukuda, Hitomi Moriyama, Shizuko Kakinuma, Masahiro Fukushi, Yoshiya Shimada
The PI3K/AKT pathway is one of the most important signaling networks in human breast cancer, and since it was potentially implicated in our preliminary investigations of radiation-induced rat mammary carcinomas, our aim here was to verify its role. We included mammary carcinomas induced by the chemical carcinogen 1-methyl-1-nitrosourea to determine whether any changes were radiation-specific. Most carcinomas from both groups showed activation of the PI3K/AKT pathway, but phosphorylation of AKT1 was often heterogeneous and only present in a minority of carcinoma cells...
October 13, 2016: Journal of Radiation Research
https://www.readbyqxmd.com/read/27722144/effect-of-n-methyl-n-nitrosourea-on-helicobacter-induced-gastric-carcinogenesis-in-c57bl-6-mice
#18
Ju Yup Lee, Nayoung Kim, Yoon Jeong Choi, Ryoung Hee Nam, Yoon Jin Choi, Seonmin Lee, Daeun Choi, Hye Seung Lee, Jin-Wook Kim, Dong Ho Lee
BACKGROUND: The aim of this study was to investigate the effect of N-methyl-N-nitrosourea (MNU) treatment followed by chronic Helicobacter pylori SS1 and H. felis colonization on the stomachs of C57BL/6 mice. The role of MNU and Helicobacter species in gastric carcinogenesis was also elucidated. METHODS: A total of 69 C57BL/6 mice at 4 weeks of age were divided into 6 groups according to MNU treatment and H. pylori SS1 or H. felis infection. The mice were sacrificed at 21 and 50 weeks...
September 2016: Journal of Cancer Prevention
https://www.readbyqxmd.com/read/27708159/insulin-resistance-and-diabetes-caused-by-genetic-or-diet-induced-kbtbd2-deficiency-in-mice
#19
Zhao Zhang, Emre Turer, Xiaohong Li, Xiaoming Zhan, Mihwa Choi, Miao Tang, Amanda Press, Steven R Smith, Adeline Divoux, Eva Marie Y Moresco, Bruce Beutler
We describe a metabolic disorder characterized by lipodystrophy, hepatic steatosis, insulin resistance, severe diabetes, and growth retardation observed in mice carrying N-ethyl-N-nitrosourea (ENU)-induced mutations. The disorder was ascribed to a mutation of kelch repeat and BTB (POZ) domain containing 2 (Kbtbd2) and was mimicked by a CRISPR/Cas9-targeted null allele of the same gene. Kbtbd2 encodes a BTB-Kelch family substrate recognition subunit of the Cullin-3-based E3 ubiquitin ligase. KBTBD2 targeted p85α, the regulatory subunit of the phosphoinositol-3-kinase (PI3K) heterodimer, causing p85α ubiquitination and proteasome-mediated degradation...
October 18, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27706598/defective-eyelid-leading-edge-cell-migration-in-c57bl-6-corneal-opacity-mice-with-an-eye-open-at-birth-phenotype
#20
L C Wu, C Liu, M R Jiang, Y M Jiang, Q H Wang, Z Y Lu, S J Wang, W L Yang, Y X Shao
Development of the eyelid requires coordination of the cellular processes involved in proliferation, cell size alteration, migration, and cell death. C57BL/6J-corneal opacity (B6-Co) mice are mutant mice generated by the administration of N-ethyl-N-nitrosourea (100 mg/kg). They exhibit the eyelids open at birth phenotype, abnormal round cell shape from tightened F-actin bundles in leading edge keratinocytes at E16.5, and gradual corneal opacity with neovessels. The tip of the leading edge in B6-Co mice did not move forward, and demonstrated a sharp peak shape without obvious directionality...
August 26, 2016: Genetics and Molecular Research: GMR
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