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https://www.readbyqxmd.com/read/28820464/enhanced-susceptibility-of-ogg1-mutant-mice-to-multiorgan-carcinogenesis
#1
Anna Kakehashi, Naomi Ishii, Takahiro Okuno, Masaki Fujioka, Min Gi, Hideki Wanibuchi
The role of deficiency of oxoguanine glycosylase 1 (Ogg1) Mmh homolog, a repair enzyme of the 8-hydroxy-2'-deoxyguanosine (8-OHdG) residue in DNA, was investigated using the multiorgan carcinogenesis bioassay in mice. A total of 80 male and female six-week-old mice of C57BL/6J background carrying a mutant Mmh allele of the Mmh/Ogg1 gene (Ogg1(-)(/)(-)) and wild type (Ogg1(+/+)) mice were administered N-diethylnitrosamine (DEN), N-methyl-N-nitrosourea (MNU), N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN), N-bis (2-hydroxypropyl) nitrosamine (DHPN) and 1,2-dimethylhydrazine dihydrochloride (DMH) (DMBDD) to induce carcinogenesis in multiple organs, and observed up to 34 weeks...
August 18, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28807016/endogenous-controls-of-gene-expression-in-n-methyl-n-nitrosourea-induced-t-cell-lymphoma-in-p53-deficient-mice
#2
Xi Wu, Susu Liu, Jianjun Lyu, Shuya Zhou, Yanwei Yang, Chenfei Wang, Wenda Gu, Qin Zuo, Baowen Li, Changfa Fan
BACKGROUND: Real-time polymerase chain reaction (PCR) has become an increasingly important technique for gene expression profiling because it can provide insights into complex biological and pathological processes and be used to predict disease or treatment outcomes. Although normalized data are necessary for an accurate estimation of mRNA expression levels, several pieces of evidence suggest that the expression of so-called housekeeping genes is not stable. This study aimed to validate reference genes for the normalization of real-time PCR in an N-methyl-N-nitrosourea (MNU)-induced T-cell lymphoma mouse model...
August 14, 2017: BMC Cancer
https://www.readbyqxmd.com/read/28806779/a-mutation-in-nischarin-causes-otitis-media-via-limk1-and-nf-%C3%AE%C2%BAb-pathways
#3
Michael Crompton, Tom Purnell, Hayley E Tyrer, Andrew Parker, Greg Ball, Rachel E Hardisty-Hughes, Richard Gale, Debbie Williams, Charlotte H Dean, Michelle M Simon, Ann-Marie Mallon, Sara Wells, Mahmood F Bhutta, Martin J Burton, Hilda Tateossian, Steve D M Brown
Otitis media (OM), inflammation of the middle ear (ME), is a common cause of conductive hearing impairment. Despite the importance of the disease, the aetiology of chronic and recurrent forms of middle ear inflammatory disease remains poorly understood. Studies of the human population suggest that there is a significant genetic component predisposing to the development of chronic OM, although the underlying genes are largely unknown. Using N-ethyl-N-nitrosourea mutagenesis we identified a recessive mouse mutant, edison, that spontaneously develops a conductive hearing loss due to chronic OM...
August 14, 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28797121/non-alcoholic-fatty-liver-disease-in-mice-with-heterozygous-mutation-in-tmed2
#4
Wenyang Hou, Swati Gupta, Marie-Claude Beauchamp, Libin Yuan, Loydie A Jerome-Majewska
The transmembrane emp24 domain/p24 (TMED) family are essential components of the vesicular transport machinery. Members of the TMED family serve as cargo receptors implicated in selection and packaging of endoplasmic reticulum (ER) luminal proteins into coatomer (COP) II coated vesicles for anterograde transport to the Golgi. Deletion or mutations of Tmed genes in yeast and Drosophila results in ER-stress and activation of the unfolded protein response (UPR). The UPR leads to expression of genes and proteins important for expanding the folding capacity of the ER, degrading misfolded proteins, and reducing the load of new proteins entering the ER...
2017: PloS One
https://www.readbyqxmd.com/read/28751539/mechanisms-of-resistance-to-ntrk-inhibitors-and-therapeutic-strategies-in-ntrk1-rearranged-cancers
#5
Miho J Fuse, Koutaroh Okada, Tomoko Oh-Hara, Hayato Ogura, Naoya Fujita, Ryohei Katayama
Neurotrophic receptor tyrosine kinase 1 (NTRK1) gene rearrangement leads to constitutive activation of NTRK1, which induces high transforming ability. NTRK-rearranged cancers have been identified in several cancer types, such as glioblastoma, non-small-cell lung cancer, and colorectal cancer. Although there are currently no clinically approved inhibitors that target NTRK1, several tyrosine kinase inhibitors (TKIs), such as entrectinib and LOXO-101, are in clinical trials. The purpose of this study was to identify potential mechanisms of resistance to NTRK inhibitors and find potential therapeutic strategies to overcome the resistance...
July 27, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28744879/procarbazine-lomustine-and-vincristine-for-recurrent-high-grade-glioma
#6
REVIEW
Saurabh Parasramka, Goutham Talari, Myrna Rosenfeld, Jing Guo, John L Villano
BACKGROUND: Recurrent high-grade glioma (HGG) carries an extremely poor prognosis. There is no current standard of care or guideline-based recommendations. Nitrosourea-based multidrug chemotherapy or PCV - procarbazine, lomustine (CCNU) and vincristine - is one of the treatment options at recurrence. There has been no meta-analysis which looks at the benefits and harms of PCV chemotherapy in adults with recurrent HGG. OBJECTIVES: To assess the effectiveness and safety of procarbazine, lomustine, and vincristine (PCV) chemotherapy with other interventions in adults with recurrent high-grade glioma...
July 26, 2017: Cochrane Database of Systematic Reviews
https://www.readbyqxmd.com/read/28717217/tki-addicted-ros1-rearranged-cells-are-destined-to-survival-or-death-by-the-intensity-of-ros1-kinase-activity
#7
Hayato Ogura, Yuka Nagatake-Kobayashi, Jun Adachi, Takeshi Tomonaga, Naoya Fujita, Ryohei Katayama
ROS1 rearrangement is observed in 1-2% of non-small cell lung cancers (NSCLC). The ROS1 tyrosine kinase inhibitor (TKI) crizotinib has induced marked tumour shrinkage in ROS1-rearranged cancers. However, emergence of acquired resistance to TKI is inevitable within a few years. Previous findings indicate that cabozantinib overcomes secondary mutation-mediated crizotinib-resistance in ROS1-fusion-positive cells. Here we attempted to establish cabozantinib-resistant cells by N-ethyl-N-nitrosourea mutagenesis screening using CD74-ROS1-expressing Ba/F3 cells...
July 17, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28714084/applying-the-erythrocyte-pig-a-assay-concept-to-rat-epididymal-sperm-for-germ-cell-mutagenicity-evaluation
#8
Zhiying Ji, Matthew J LeBaron
The Pig-a assay, a recently developed in vivo somatic gene mutation assay, is based on the identification of mutant erythrocytes that have an altered repertoire of glycosylphosphatidylinositol (GPI)-anchored cell surface markers. We hypothesized that the erythrocyte Pig-a assay concept could be applied to rat cauda epididymal spermatozoa (sperm) for germ cell mutagenicity evaluation. We used GPI-anchored CD59 as the Pig-a mutation marker and examined the frequency of CD59-negative sperm using flow cytometry...
July 17, 2017: Environmental and Molecular Mutagenesis
https://www.readbyqxmd.com/read/28711606/ovarian-aromatase-loss-of-function-mutant-medaka-undergo-ovary-degeneration-and-partial-female-to-male-sex-reversal-after-puberty
#9
Masatoshi Nakamoto, Yasushi Shibata, Kaoru Ohno, Takeshi Usami, Yasuhiro Kamei, Yoshihito Taniguchi, Takeshi Todo, Takashi Sakamoto, Graham Young, Penny Swanson, Kiyoshi Naruse, Yoshitaka Nagahama
Although estrogens have been generally considered to play a critical role in ovarian differentiation in non-mammalian vertebrates, the specific functions of estrogens during ovarian differentiation remain unclear. We isolated two mutants with premature stops in the ovarian aromatase (cyp19a1) gene from an N-ethyl-N-nitrosourea-based gene-driven mutagenesis library of the medaka, Oryzias latipes. In XX mutants, gonads first differentiated into normal ovaries containing many ovarian follicles that failed to accumulate yolk...
July 12, 2017: Molecular and Cellular Endocrinology
https://www.readbyqxmd.com/read/28694663/inhibition-of-n-methyl-n-nitrosourea-induced-gastric-tumorigenesis-by-liuwei-dihuang-pill-in-db-db-mice
#10
Shan Zhuang, Yong-Mei Jian, Yong-Ning Sun
AIM: To investigate the inhibitory effect of Liuwei Dihuang Pill (LDP) on gastric tumorigenesis induced by N-methyl-N-nitrosourea (MNU) in diabetic mice. METHODS: Four-week-old mice were divided into four groups: A, 12 db/m mice treated with MNU and saline, as the non-diabetic control; B, 12 db/db mice treated with MNU and saline, as the diabetic control; C, 12 db/db mice treated with MNU and metformin, as the positive control; and D, 12 db/db mice treated with MNU and LDP...
June 21, 2017: World Journal of Gastroenterology: WJG
https://www.readbyqxmd.com/read/28690194/examining-a-role-for-pkg-i%C3%AE-oxidation-in-the-pathogenesis-of-cardiovascular-dysfunction-during-diet-induced-obesity
#11
Olena Rudyk, Philip Eaton
BACKGROUND: Protein kinase G (PKG) Iα is the end-effector kinase that mediates nitric oxide (NO)-dependent and oxidant-dependent vasorelaxation to maintain blood pressure during health. A hallmark of cardiovascular disease is attenuated NO production, which in part is caused by NO Synthase (NOS) uncoupling, which in turn increases oxidative stress because of superoxide generation. NOS uncoupling promotes PKG Iα oxidation to the interprotein disulfide state, likely mediated by superoxide-derived hydrogen peroxide, and because the NO-cyclic guanosine monophosphate (cGMP) pathway otherwise negatively regulates oxidation of the kinase to its active disulfide dimeric state...
September 2017: Free Radical Biology & Medicine
https://www.readbyqxmd.com/read/28688903/differential-effects-between-developmental-and-postpubertal-exposure-to-n-methyl-n-nitrosourea-on-progenitor-cell-proliferation-of-rat-hippocampal-neurogenesis-in-relation-to-cox2-expression-in-granule-cells
#12
Yousuke Watanabe, Kota Nakajima, Sayaka Mizukami, Yumi Akahori, Nobuya Imatanaka, Gye-Hyeong Woo, Toshinori Yoshida, Makoto Shibutani
This study was performed to compare the exposure effects of N-methyl-N-nitrosourea (MNU), a cytocidal agent of proliferating cells, on rat hippocampal neurogenesis between developmental and postpubertal periods. Developmental exposure through maternal drinking water from gestational day 6 to day 21 after delivery on weaning decreased GFAP-immunoreactive ((+)) stem cells and increased immunoreactive cells indicative of subsequent progenitor and postmitotic immature neuronal populations, TUNEL(+) or p21(Cip1/Waf1+) stem/progenitor cells and COX2(+) granule cells, on postnatal day (PND) 21...
July 6, 2017: Toxicology
https://www.readbyqxmd.com/read/28687238/assessment-of-the-mutagenic-potential-of-hexavalent-chromium-in-the-duodenum-of-big-blue%C3%A2-rats
#13
Chad M Thompson, Robert R Young, Harshini Dinesdurage, Mina Suh, Mark A Harris, Annette C Rohr, Deborah M Proctor
A cancer bioassay on hexavalent chromium Cr(VI) in drinking water reported increased incidences of duodenal tumors in B6C3F1 mice at exposures of 30-180ppm, and oral cavity tumors in F344 rats at 180ppm. A subsequent transgenic rodent (TGR) in vivo mutation assay in Big Blue® TgF344 rats found that exposure to 180ppm Cr(VI) in drinking water for 28days did not increase cII transgene mutant frequency (MF) in the oral cavity (Thompson et al., 2015). Herein, we extend our analysis to the duodenum of these same TgF344 rats...
September 1, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/28672195/combination-treatment-with-the-gsk-3-inhibitor-9-ing-41-and-ccnu-cures-orthotopic-chemoresistant-glioblastoma-in-patient-derived-xenograft-models
#14
Andrey Ugolkov, Wenan Qiang, Gennadiy Bondarenko, Daniel Procissi, Irina Gaisina, C David James, James Chandler, Alan Kozikowski, Hendra Gunosewoyo, Thomas O'Halloran, Jeffrey Raizer, Andrew P Mazar
Resistance to chemotherapy remains a major challenge in the treatment of human glioblastoma (GBM). Glycogen synthase kinase-3β (GSK-3β), a positive regulator of NF-κB-mediated survival and chemoresistance of cancer cells, has been identified as a potential therapeutic target in human GBM. Our objective was to determine the antitumor effect of GSK-3 inhibitor 9-ING-41 in combination with chemotherapy in patient-derived xenograft (PDX) models of human GBM. We utilized chemoresistant PDX models of GBM, GBM6 and GBM12, to study the effect of 9-ING-41 used alone and in combination with chemotherapy on tumor progression and survival...
August 2017: Translational Oncology
https://www.readbyqxmd.com/read/28668849/impact-of-physical-training-on-sex-hormones-and-their-receptors-during-n-methyl-n-nitrosourea-induced-carcinogenesis-in-rats
#15
Iwona Malicka, Katarzyna Siewierska, Christopher Kobierzycki, Jedrzej Grzegrzolka, Aleksandra Piotrowska, Urszula Paslawska, Marek Cegielski, Piotr Dziegiel, Marzenna Podhorska-Okolow, Marek Wozniewski
BACKGROUND/AIM: The risk of breast cancer is related to duration of exposure to sex hormones, especially estrogen. The aim of this study was to assess the impact of physical training (PT) on estrogen and progesterone levels and expression of their receptors during carcinogenesis induced by N-methyl-N-nitrosourea (MNU) in rats. MATERIALS AND METHODS: Fifty female Sprague-Dawley rats were intraperitoneally administered MNU and divided into four groups: low-, moderate-, and high-intensity PT, and no PT (control)...
July 2017: Anticancer Research
https://www.readbyqxmd.com/read/28646597/a-contrast-enhanced-ultrasonographic-study-about-the-impact-of-long-term-exercise-training-on-mammary-tumor-vascularization
#16
Ana I Faustino-Rocha, Adelina Gama, Paula A Oliveira, Katrien Vanderperren, Jimmy H Saunders, Maria J Pires, Rita Ferreira, Mário Ginja
OBJECTIVES: This study aimed to evaluate the impact of long-term exercise training on the vascularization of rat mammary tumors. METHODS: Female rats were divided into 4 groups: N-methyl-N-nitrosourea (MNU) treated sedentary, MNU treated exercised, control sedentary, and control exercised. Tumor development was induced in the MNU groups by MNU administration. Exercised groups were trained for 35 weeks. Tumor vascularization was evaluated by pulsed Doppler and contrast-enhanced ultrasonography...
June 24, 2017: Journal of Ultrasound in Medicine: Official Journal of the American Institute of Ultrasound in Medicine
https://www.readbyqxmd.com/read/28639938/pilot-study-of-large-scale-production-of-mutant-pigs-by-enu-mutagenesis
#17
Tang Hai, Chunwei Cao, Haitao Shang, Weiwei Guo, Yanshuang Mu, Shulin Yang, Ying Zhang, Qiantao Zheng, Tao Zhang, Xianlong Wang, Yu Liu, Qingran Kong, Kui Li, Dayu Wang, Meng Qi, Qianlong Hong, Rui Zhang, Xiupeng Wang, Qitao Jia, Xiao Wang, Guosong Qin, Yongshun Li, Ailing Luo, Weiwu Jin, Jing Yao, Jiaojiao Huang, Hongyong Zhang, Menghua Li, Xiangmo Xie, Xuejuan Zheng, Kenan Guo, Qinghua Wang, Shibin Zhang, Liang Li, Fei Xie, Yu Zhang, Xiaogang Weng, Zhi Yin, Kui Hu, Yimei Cong, Peng Zheng, Hailong Zou, Leilei Xin, Jihan Xia, Jinxue Ruan, Hegang Li, Weiming Zhao, Jing Yuan, Zizhan Liu, Weiwang Gu, Ming Li, Yong Wang, Hongmei Wang, Shiming Yang, Zhonghua Liu, Hong Wei, Jianguo Zhao, Qi Zhou, Anming Meng
N-ethyl-N-nitrosourea (ENU) mutagenesis is a powerful tool to generate mutants on a large scale efficiently, and to discover genes with novel functions at the whole-genome level in Caenorhabditis elegans, flies, zebrafish and mice, but it has never been tried in large model animals. We describe a successful systematic three-generation ENU mutagenesis screening in pigs with the establishment of the Chinese Swine Mutagenesis Consortium. A total of 6,770 G1 and 6,800 G3 pigs were screened, 36 dominant and 91 recessive novel pig families with various phenotypes were established...
June 22, 2017: ELife
https://www.readbyqxmd.com/read/28622829/investigation-of-j-shaped-dose-responses-induced-by-exposure-to-the-alkylating-agent-n-methyl-n-nitrosourea
#18
Katherine E Chapman, George R Hoffmann, Shareen H Doak, Gareth J S Jenkins
Hormesis is defined as a biphasic dose-response where biological effects of low doses of a stressor demonstrate the opposite effect to high-dose effects of the same stressor. Hormetic, or J-shaped, dose-response relationships are relatively rarely observed in toxicology, resulting in a limited understanding and even some skepticism of the concept. Low dose-response studies for genotoxicity endpoints have been performed at Swansea University for over a decade. However, no statistically significant decreases below control genotoxicity levels have been detected until recently...
July 2017: Mutation Research
https://www.readbyqxmd.com/read/28612574/-optimization-ofpig-agene-mutation-in-rats-and-assessment-of-time-dependent-and-dose-response-relationship-of-n-ethyl-n-nitrosourea
#19
Si-Jia Ma, Jiao Huo, Jin-Yao Chen, Qi-Yan Chen, Li-Shi Zhang
OBJECTIVES: To optimize the method of Pig-a mutation assay, and to explore the time-dependent and dose-response relationship of N-ethyl-N-nitrosourea (ENU). METHODS: Thirty rats were randomly assigned to 5 groups: treated with PBS (control group)or different doses of ENU (10, 20, 40 and 80 mg/kg) for 3 d by oral gavage. Blood samples were collected at 0 d, 15 d, 30 d, 45 d, 60 d, 75 d and 90 d. After enrichment, erythrocytes were incubated with Anti-CD59-APC and SYTO 13 nucleic acid dye solution...
January 2017: Sichuan da Xue Xue Bao. Yi Xue Ban, Journal of Sichuan University. Medical Science Edition
https://www.readbyqxmd.com/read/28607088/skin-specific-regulation-of-srebp-processing-and-lipid-biosynthesis-by-glycerol-kinase-5
#20
Duanwu Zhang, Wataru Tomisato, Lijing Su, Lei Sun, Jin Huk Choi, Zhao Zhang, Kuan-Wen Wang, Xiaoming Zhan, Mihwa Choi, Xiaohong Li, Miao Tang, Jose M Castro-Perez, Sara Hildebrand, Anne R Murray, Eva Marie Y Moresco, Bruce Beutler
The recessive N-ethyl-N-nitrosourea-induced phenotype toku is characterized by delayed hair growth, progressive hair loss, and excessive accumulation of dermal cholesterol, triglycerides, and ceramides. The toku phenotype was attributed to a null allele of Gk5, encoding glycerol kinase 5 (GK5), a skin-specific kinase expressed predominantly in sebaceous glands. GK5 formed a complex with the sterol regulatory element-binding proteins (SREBPs) through their C-terminal regulatory domains, inhibiting SREBP processing and activation...
June 27, 2017: Proceedings of the National Academy of Sciences of the United States of America
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