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Kazumasa Honda, Masato Naya, Hiroshi Takehara, Hiromichi Kataura, Katsuhide Fujita, Makoto Ema
We compared long-term pulmonary toxicities after a single intratracheal instillation of two types of dispersed single-wall carbon nanotubes (SWCNTs), namely, those with relatively long or short linear shapes with average lengths of 8.6 and 0.55 µm, respectively. Both types of SWCNTs were instilled intratracheally in male F344 rats at 0.2 or 1.0 mg/kg (long SWCNTs) or 1.0 mg/kg (short SWCNTs). Pulmonary responses were characterized at 26, 52 and 104 weeks after a single instillation. Inflammatory changes, test substance deposition, test substance engulfment by macrophages, and alveolar wall fibrosis were observed in the lungs of almost all test rats at 52 and 104 weeks after short nanotube instillation...
November 7, 2017: Inhalation Toxicology
Masanao Yokohira, Yuko Nakano-Narusawa, Keiko Yamakawa, Nozomi Hashimoto, Shota Yoshida, Shohei Kanie, Katsumi Imaida
There are two types of bronchiolo-alveolar hyperplasia (hyperplasia) in rodent lungs. The first is "inflammatory hyperplasia" that retains its ability to revert to normal epithelia upon removal of the stimulating insult. The second is "latent tumorigenic hyperplasia", which is irreversible and causes independent preneoplastic lesions that can progress to bronchiolo-alveolar adenocarcinoma. Previously, lung samples with hyperplastic lesions were obtained from rats exposed to N-bis (2-hydroxypropyl) nitrosamine (DHPN) and fine particles (e...
October 2, 2017: Experimental and Toxicologic Pathology: Official Journal of the Gesellschaft Für Toxikologische Pathologie
Tomoya Yamada, Miwa Kondo, Kaori Miyata, Keiko Ogata, Masahiko Kushida, Kayo Sumida, Satoshi Kawamura, Thomas G Osimitz, Brian G Lake, Samuel M Cohen
Permethrin increased the incidence of bronchiolo-alveolar adenomas in female mice but not male mice or female or male rats. Studies were conducted to determine whether permethrin has mitogenic activity in Club cells in mouse lung as the basis for the mode of action (MOA) for the lung adenoma induction. Several short-term experiments focusing on time-course, dose-response, reversibility, sex difference, strain difference, and species difference were evaluated for Club cell proliferation and morphology. The findings demonstrated that permethrin slightly and continuously enhanced Club cell proliferation at tumor-associated dose levels in female mice, but did not increase proliferation in male mice or in female rats...
June 1, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
Mayuko Suguro, Takamasa Numano, Mayumi Kawabe, Yuko Doi, Norio Imai, Yukinori Mera, Seiko Tamano
Short-term alternatives to traditional 2-year carcinogenic studies in rodents are being actively pursued. Recently, a 26-week short-term carcinogenicity study using CB6F1-Tg rasH2@Jcl (rasH2) mice has become a worldwide standard for the evaluation of chemical carcinogenesis. However, an acceptable short-term carcinogenic study model for dermally applied products is still lacking. To investigate the suitability of using the rasH2 mouse to test carcinogenic potential, 1,2-dichloroethane (1,2-DCE) was dermally applied to rasH2 mice: 1,2-DCE is a known carcinogen that causes lung bronchiolo-alveolar adenomas and adenocarcinomas when administered topically, orally, or by inhalation exposure; 1,2-DCE at a dose level of 126 mg/mouse in 200 μl acetone or acetone alone (vehicle control) was applied to the dorsal skin of 10 mice of each sex 3 times a week for 26 weeks...
April 2017: Toxicologic Pathology
Tatsuya Kasai, Yumi Umeda, Makoto Ohnishi, Takashi Mine, Hitomi Kondo, Tetsuya Takeuchi, Michiharu Matsumoto, Shoji Fukushima
BACKGROUND: Multi-walled carbon nanotubes (MWCNTs) constitute one of the most promising types of nanomaterials in industry today. With their increasing use, the potential toxicity and carcinogenicity of MWCNT needs to be evaluated in bioassay studies using rodents. Since humans are mainly exposed to MWCNT by inhalation, we performed a 104-week carcinogenicity study using whole-body inhalation exposure chambers with a fibrous straight type of MWCNT at concentrations of 0, 0.02, 0.2, and 2 mg/m(3) using male and female F344 rats...
October 13, 2016: Particle and Fibre Toxicology
Christopher M Evans, Tasha E Fingerlin, Marvin I Schwarz, David Lynch, Jonathan Kurche, Laura Warg, Ivana V Yang, David A Schwartz
Idiopathic pulmonary fibrosis (IPF) is an incurable complex genetic disorder that is associated with sequence changes in 7 genes (MUC5B, TERT, TERC, RTEL1, PARN, SFTPC, and SFTPA2) and with variants in at least 11 novel loci. We have previously found that 1) a common gain-of-function promoter variant in MUC5B rs35705950 is the strongest risk factor (genetic and otherwise), accounting for 30-35% of the risk of developing IPF, a disease that was previously considered idiopathic; 2) the MUC5B promoter variant can potentially be used to identify individuals with preclinical pulmonary fibrosis and is predictive of radiologic progression of preclinical pulmonary fibrosis; and 3) MUC5B may be involved in the pathogenesis of pulmonary fibrosis with MUC5B message and protein expressed in bronchiolo-alveolar epithelia of IPF and the characteristic IPF honeycomb cysts...
October 2016: Physiological Reviews
Christian Strupp, Werner Bomann, Samuel M Cohen, Klaus Weber
Fluensulfone is a nematicide for agricultural use. Chronic dietary exposure led to bronchiolo-alveolar hyperplasia and bronchiolo-alveolar adenomas in CD-1 mice but not in rats. Genotoxicity could be excluded as a mode of action (MOA). An earlier publication (Strupp, C., Banas, D. A., Cohen, S. M., Gordon, E. B., Jaeger, M., and Weber, K. (2012). Relationship of metabolism and cell proliferation to the mode of action of fluensulfone-induced mouse lung tumors: analysis of their human relevance using the IPCS framework...
December 2016: Toxicological Sciences: An Official Journal of the Society of Toxicology
Chanida Vinayanuwattikun, Florence Le Calvez-Kelm, Behnoush Abedi-Ardekani, David Zaridze, Anush Mukeria, Catherine Voegele, Maxime Vallée, Dewajani Purnomosari, Nathalie Forey, Geoffroy Durand, Graham Byrnes, James Mckay, Paul Brennan, Ghislaine Scelo
To examine the diversity of somatic alterations and clonal evolution according to aggressiveness of disease, nineteen tumor-blood pairs of 'formerly bronchiolo-alveolar carcinoma (BAC)' which had been reclassified into preinvasive lesion (adenocarcinoma in situ; AIS), focal invasive lesion (minimally invasive adenocarcinoma; MIA), and invasive lesion (lepidic predominant adenocarcinoma; LPA and non-lepidic predominant adenocarcinoma; non-LPA) according to IASLC/ATS/ERS 2011 classification were explored by whole exome sequencing...
August 22, 2016: Scientific Reports
Ernst M Bomhard
Indium tin oxide (ITO) is a technologically important semiconductor. An increasing number of cases of severe lung effects (characterized by pulmonary alveolar proteinosis and/or interstitial fibrosis) in ITO-exposed workers warrants a review of the toxicological hazards. Short- and long-term inhalation studies in rats and mice revealed persistent alveolar proteinosis, inflammation and fibrosis in the lungs down to concentrations as low as 0.01mg/m(3). In rats, the incidences of bronchiolo-alveolar adenomas and carcinomas were significantly increased at all concentrations...
July 2016: Environmental Toxicology and Pharmacology
Masumi Suzui, Mitsuru Futakuchi, Katsumi Fukamachi, Takamasa Numano, Mohamed Abdelgied, Satoru Takahashi, Makoto Ohnishi, Toyonori Omori, Shuji Tsuruoka, Akihiko Hirose, Jun Kanno, Yoshimitsu Sakamoto, David B Alexander, William T Alexander, Xu Jiegou, Hiroyuki Tsuda
Multiwalled carbon nanotubes (MWCNT) have a fibrous structure and physical properties similar to asbestos and have been shown to induce malignant mesothelioma of the peritoneum after injection into the scrotum or peritoneal cavity in rats and mice. For human cancer risk assessment, however, data after administration of MWCNT via the airway, the exposure route that is most relevant to humans, is required. The present study was undertaken to investigate the carcinogenicity of MWCNT-N (NIKKISO) after administration to the rat lung...
July 2016: Cancer Science
Nicolas Berthet, Lionel Frangeul, Ken André Olaussen, Elisabeth Brambilla, Nicolas Dorvault, Philippe Girard, Pierre Validire, Elie Fadel, Christiane Bouchier, Antoine Gessain, Jean-Charles Soria
BACKGROUND: The hypothesis of an infectious etiology of the formerly named bronchiolo-alveolar carcinoma (BAC) has raised controversy. We investigated tumor lung tissues from five patients with former BAC histology using high-throughput sequencing technologies to discover potential viruses present in this type of lung cancer. Around 180 million single reads of 100 bases were generated for each BAC sample. RESULTS: None of the reads showed a significant similarity for Jaagsiekte sheep retrovirus (JSRV) and no other viruses were found except for endogenous retroviruses...
2015: BMC Research Notes
G Le Bars, S Dion, B Gauthier, S Mhedhbi, G Pohlmeyer-Esch, P Comby, N Vivan, B Ruty
Miglyol 812(®), a mixture of medium-chain triglycerides, has been identified as an oral vehicle that could improve the solubility and possibly the bioavailability of orally administered drugs during the non-clinical safety assessment. The toxicity of Miglyol was assessed in Göttingen(®) minipigs upon daily oral administration (gavage) for six weeks, at dosing-volumes of 0.5 and 2 mL/kg/day, compared to controls receiving 0.5% CarboxyMethylCellulose/0.1% Tween(®) 80 in water at 2 mL/kg/day. The control vehicle did not induce any findings...
December 2015: Regulatory Toxicology and Pharmacology: RTP
Kay E Gurley, Russell D Moser, Christopher J Kemp
In this protocol, urethane (ethyl carbamate) is used to induce lung tumors in mice. The use of urethane as an experimental carcinogen is especially attractive as it is inexpensive, relatively safe to handle, stable, and water soluble, and the protocol involves simple intraperitoneal (i.p.) injections in young mice. Urethane typically induces bronchioalveolar adenomas and, to a lesser extent, adenocarcinomas that resemble the adenocarcinoma subtype of non-small cell lung carcinoma. On a sensitive genetic background such as A/J, mice develop multiple adenomas visible on the lung surface by 25 wk, followed by the appearance of adenocarcinomas by 40 wk...
September 1, 2015: Cold Spring Harbor Protocols
Yasmeen M Butt, Timothy Craig Allen
CONTEXT: Bronchioloalveolar carcinoma is a term that has served lung pathology well for almost a century; however, more accurate terms have recently been suggested to better characterize the various lesions that have formerly all been considered bronchioloalveolar carcinoma. OBJECTIVES: To evaluate the origin and history of the term bronchioloalveolar carcinoma and to compare the term's traditional uses with current understanding and terminology of lung lesions formerly termed bronchioloalveolar carcinoma...
August 2015: Archives of Pathology & Laboratory Medicine
Trond-Eirik Strand, Hans Rostad, Erik H Strøm, Philip Hasleton
BACKGROUND: The literature is inconclusive as to whether the percentage of the lepidic component of an invasive adenocarcinoma (AC) of the lung influences prognosis. We studied a population-based series of selected, resected invasive pulmonary ACs to determine if incremental increases in the lepidic component were an independent, prognostic variable. METHODS: Patients undergoing resection for lung cancer reported to the Cancer Registry of Norway and diagnosed in the period 1993-2002 with a bronchioloalveolar carcinoma (BAC) (old terminology) (adenocarcinoma in situ, AIS in the new terminology) in the lung were selected...
2015: Diagnostic Pathology
Beibei Chu, Jiang Wang, Yueying Wang, Guoyu Yang
The M2 isoform of pyruvate kinase (PKM2), which has been identified as the predominant cause of the Warburg effect in cancer cells, is essential in tumor metabolism and growth. However, the role of PKM2 in autophagy remains to be elucidated. The present study investigated the effect of PKM2 knockdown on autophagy and apoptotic cell death in human A549 alveolar adenocarcinoma cells. Two short hairpin (sh)RNAs targeting human PKM2 mRNA were designed and lentiviral vectors were constructed. The A549 cells were infected with lentiviruses, containing shRNAs against PKM2, and the expression of PKM2 was examined by reverse transcription-quantitative polymerase chain reaction (RT‑qPCR) and immonoblotting analysis...
September 2015: Molecular Medicine Reports
Hue-Hua L Hong, Mark J Hoenerhoff, Thai-Vu Ton, Ronald A Herbert, Grace E Kissling, Michelle J Hooth, Mamta Behl, Kristine L Witt, Stephanie L Smith-Roe, Robert C Sills, Arun R Pandiri
Rodent lung tumors are morphologically similar to a subtype of human lung adenocarcinomas. The objective of this study was to evaluate Kirsten rat sarcoma oncogene homolog (Kras), epidermal growth factor receptor (Egfr), and tumor protein 53 (Tp53) mutations, which are relevant to human lung cancer, in cobalt metal dust (CMD)-induced alveolar/bronchiolar tumors of B6C3F1/N mice and F344/NTac rats. Kras mutations were detected in 67% (mice) and 31% (rats) of CMD-induced lung tumors and were predominantly exon 1 codon 12 G to T transversions (80% in mice and 57% in rats)...
August 2015: Toxicologic Pathology
Tomoko Okubo, Mitsugu Hosaka, Dai Nakae
The present study examined the effects induced in vitro in human adenocarcinoma-derived alveolar basal epithelial A549 cells by diesel particulate matter (DPM) administered into the culture medium or by diesel exhaust administered at an air-liquid interface. When A549 cells were exposed to DPM in the culture medium, cell proliferation was inhibited at doses of 10-100 μg/mL; generation of interleukin (IL)-8 and the antioxidant enzyme, heme oxygenase-1 (HO-1), were inhibited at a dose of 100 μg/mL, and hydroxyl radicals were produced, but could be inhibited by catalase or superoxide dismutase...
July 2015: Experimental and Toxicologic Pathology: Official Journal of the Gesellschaft Für Toxikologische Pathologie
Brandi N Snyder-Talkington, Chunlin Dong, Linda M Sargent, Dale W Porter, Lauren M Staska, Ann F Hubbs, Rebecca Raese, Walter McKinney, Bean T Chen, Lori Battelli, David T Lowry, Steven H Reynolds, Vincent Castranova, Yong Qian, Nancy L Guo
Inhalation exposure to multi-walled carbon nanotubes (MWCNT) in mice results in inflammation, fibrosis and the promotion of lung adenocarcinoma; however, the molecular basis behind these pathologies is unknown. This study determined global mRNA and miRNA profiles in whole blood from mice exposed by inhalation to MWCNT that correlated with the presence of lung hyperplasia, fibrosis, and bronchiolo-alveolar adenoma and adenocarcinoma. Six-week-old, male, B6C3F1 mice received a single intraperitoneal injection of either the DNA-damaging agent methylcholanthrene (MCA, 10 µg g(-1) body weight) or vehicle (corn oil)...
January 2016: Journal of Applied Toxicology: JAT
A Murphy, K Sheehy, A Casey, G Chambers
Nanotechnology is a rapidly growing field with silver nanoparticles (AgNP) in particular utilized in a wide variety of consumer products. This has presented a number of concerns relating to exposure and the associated toxicity to humans and the environment. As inhalation is the most common exposure route, this study investigates the potential toxicity of AgNP to A549 alveolar epithelial carcinoma cells and the influence of a major component of lung surfactant dipalmitoylphosphatidylcholine (DPPC) on toxicity...
October 2015: Journal of Applied Toxicology: JAT
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