Crystalline silica (quartz) is known to induce silicosis and cancer in the lungs. In the present study, we investigated the relationship between quartz-induced chronic inflammation and lung ...carcinogenesis in rat lungs after a single exposure to quartz. F344 rats were treated with a single intratracheal instillation (i.t.) of quartz (4 mg/rat), and control rats were treated with a single i.t. of saline. After 52 or 96 weeks, the animals were sacrificed, and the lungs and other organs were used for analyses. Quartz particles were observed in the lungs of all quartz-treated rats. According to our scoring system, the lungs of rats treated with quartz had higher scores for infiltration of lymphocytes, macrophages and neutrophils, oedema, fibrosis, and granuloma than the lungs of control rats. After 96 weeks, the quartz-treated rats had higher incidences of adenoma (85.7%) and adenocarcinoma (81.0%) than control rats (20% and 20%, respectively). Quartz-treated and control rats did not show lung neoplastic lesions at 52 weeks after treatment. The number of lung neoplastic lesions per rat positively correlated with the degree of macrophage and lymphocyte infiltration, oedema, fibrosis, and lymph follicle formation around the bronchioles. In conclusion, single i.t. of quartz may induce lung cancer in rat along with chronic inflammation.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The adaptor protein GAREM has two subtypes. Each is involved in Erk activation signaling downstream of the cell growth factor receptor in cultured cells. Regarding their role in individual animals, ...we have previously reported that mice deficient in GAREM2, which is highly expressed in the brain, exhibit emotional changes. In this paper, we report an amino acid substitution mutation (K291R) in GAREM1, in a patient with idiopathic short stature, which indicates that the mutant exhibits dominant-negative properties. The GAREM K291R mutant did not promote Erk activation in EGF-stimulated cultured cells. Similar features were also observed in cells in which GAREM1 expression was suppressed by genome editing; along with Erk, phosphorylation of S6 kinase and 4EBP1, whose activation is necessary for cell proliferation and biological growth, were inhibited Furthermore, we generated mice deficient in GAREM1 and showed that the mutant mice are lighter in weight.
Overall, the results of this paper suggest that GAREM1 is required for normal growth and for maintaing average body size in humans and mice.
•GAREM1 K291R mutation was found in patients with idiopathic short stature.•GAREM1 K291R mutant had reduced ability to transmit cell growth factor signals.•Cultured cells that eliminated GAREM1 expression by genome editing grew slower.•GAREM1 knockout mice had less body weight compared to wild type.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Approximately 30% of pancreatic cancer patients harbor targetable mutations. However, there has been no therapy targeting these molecules clinically. Nucleic acid medicines show high specificity and ...can target RNAs. Nucleic acid medicine is expected to be the next-generation treatment next to small molecules and antibodies. There are several kinds of nucleic acid drugs, including antisense oligonucleotides, small interfering RNAs, microRNAs, aptamers, decoys, and CpG oligodeoxynucleotides. In this review, we provide an update on current research of nucleic acid-based therapies. Despite the challenging obstacles, we hope that nucleic acid drugs will have a significant impact on the treatment of pancreatic cancer. The combination of genetic diagnosis using next generation sequencing and targeted therapy may provide effective precision medicine for pancreatic cancer patients.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Telomeres are tandem repeats of the TTAGGG sequence at chromosomal ends and afford protection against chromosomal instability. To investigate the contribution of telomere dysfunction in meningiomas, ...here we estimate the associations between telomere length, tumor grade, and proliferation index in a series of 14 archived samples, using quantitative-fluorescence in situ hybridization, Ki67 immunostaining, and pathological analysis. The number of mitoses per 10 high-power fields (HPF) and Ki67 index was higher in grade III cases than in grade I or grade II cases. Telomere length was negatively associated with both the number of mitoses/10HPF and Ki67 index. Meningioma cases with atypical mitosis, a morphological marker of chromosomal instability, exhibited shortened telomeres. Among telomere-shortened meningioma cases, 40% were grade I, 20% were grade II, and 100% were grade III. In grade I or II meningiomas, shortened telomeres lacked high proliferation activity and atypical mitosis. In conclusion, telomere shortening might be pivotal in the development of high-grade meningioma. Analysis of telomere length might be a selective marker for meningiomas with high-grade malignant potential.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Standardized pathological evaluation of the regression assessment of neoadjuvant pancreatic cancer is necessary to improve prognostication and compare treatment outcomes in clinical trials. However, ...appropriate tissue sampling from surgically resected pancreatic cancer after neoadjuvant therapy has not been elucidated. We compared the tumor regression scores in the largest cancer slide determined macroscopically or histologically. We reviewed all slides and macroscopic photos of cut surfaces from resected pancreas of patients treated with neoadjuvant chemotherapy (n = 137; chemoradiotherapy or chemotherapy). The tumor regression scores (the Evans, College of American Pathologists, Japanese Pancreas Society grading systems, and Area of Residual Tumor ART score) were evaluated for the largest tumor slide determined by macroscopy or histologically as well as all slides from the resected pancreas. The largest cancer slides determined macroscopically and histologically were discrepant in 26% of the cases. Cancer cells were not detected in the largest macroscopically defined cut slides in 3%. Only ART scores assessed in the largest histological slides displayed significant difference in overall survival. We recommend obtaining the largest histological slides to provide adequate assessment for regression of neoadjuvant-treated pancreatic cancer. Sufficient sampling to detect the largest histological slides would be mandatory.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Purpose: Autofluorescence (AF) is the fluorescence of naturally occurring substances, such as nicotinamide adenine dinucleotide (NADH) and collagen. Two-photon microscopy (2PM) allows for the ...evaluation of living organs or tissues by excitation of tissue AF.Methods: In the present study, we compared AF intensities of pancreatic tissues in different culture mediums Roswell Park Memorial Institute (RPMI) 1640, 4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid (HEPES), and phosphate buffered saline (PBS) to determine the optimal conditions for observing unfixed and unstained tissues with 2PM.Results: Tissues incubated in RPMI 1640 showed the highest overall fluorescence intensity, followed by those in HEPES and PBS. Comparing the fluorescence intensities of the respective wavelengths, two broad peaks (approximately 760 nm and 860 nm) were recognized. At approximately 760 nm, acinar cells and ductal cells were observed below the surface. This wavelength primarily detects NADH. At approximately 860 nm, dense fibrous tissue was observed on the pancreatic surface, suggesting the presence of a connective tissue surrounding the pancreas.Conclusion: 2PM imaging using AF of the murine pancreas is a promising technique to provide new insights on structure and morphology.
Lung cancer remains the leading cause of cancer-related deaths, with an estimated 1.76 million deaths reported in 2018. Numerous studies have focused on the prevention and treatment of lung cancer ...using rodent models. Various chemicals, including tobacco-derived agents induce lung cancer and pre-cancerous lesions in rodents. In recent years, transgenic engineered rodents, in particular, those generated with a focus on the well-known gene mutations in human lung cancer (KRAS, EGFR, and p53 mutations) have been widely studied. Animal studies have revealed that chronic inflammation significantly enhances lung carcinogenesis, and inhibition of inflammation suppresses cancer progression. Moreover, the reduction in tumor size by suppression of inflammation in animal experiments suggests that chronic inflammation influences the promotion of tumorigenesis. Here, we review rodent lung tumor models induced by various chemical carcinogens, including tobacco-related carcinogens, and transgenics, and discuss the roles of chronic inflammation in lung carcinogenesis.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Despite advances in diagnostics and therapeutics, the prognosis of pancreatic cancer remains dismal. Because of a lack of early diagnostic methods, aggressive local progression, and high incidence of ...distant metastasis, most pancreatic cancers are inoperable; therefore, the characteristics of early pancreatic cancer have not been well understood. Autopsy studies revealed the characteristics of prediagnostic pancreatic malignancies, including precancerous lesions, early stage pancreatic cancer, and pancreatic cancer without clinical symptoms (occult cancers). Animal models using hamsters and genetically engineered mice have focused on mechanisms of carcinogenesis, thereby providing insights into risk factors and prevention and serving as a preclinical test for the development of novel diagnostic and treatment modalities. In this review, we have summarized pathological changes in the pancreas of humans and experimental animals during carcinogenesis.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Information on the safety of chemical substances in patients with various preexisting conditions remains limited. Acetaminophen was added to the basal diet at 0, 80, 253, 800, 2530, or 8000 ppm and ...administered to type 2 diabetes mellitus rats (GK/Jcl) and the control male rats (Wistar) for 13 weeks. Both strains treated with 8000 ppm acetaminophen (561.4 and 567.7 mg/kg body weight/day, GK/Jcl and Wistar rats, respectively) showed decreased levels of red blood cell counts, blood urea nitrogen, creatinine, and total bilirubin compared to those of non-treated rats. Treatment with 8000 ppm of acetaminophen reduced the blood glucose and hemoglobin A1c levels of GK/Jcl rats. An increase in the relative weights of the kidneys and liver, and a decrease in the weight of the salivary glands were observed in both GK/Jcl and Wistar rats treated with 8000 ppm acetaminophen relative to those of non-treated control rats. Microscopically, both strains treated with 2530 (174.3 and 164.2 mg/kg body weight/day, GK/Jcl and Wistar rats, respectively) or 8000 ppm acetaminophen showed hepatocellular hypertrophy and degenerative lesions in the salivary glands, whereas similar lesions were not observed in non-treated rats. In conclusion, the no-observed-adverse-effect-level of acetaminophen was 800 ppm in both diabetic and control rats.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Fiber‐shaped particles of potassium octatitanate (tradename TISMO; chemical formula K2O·6TiO2), which are morphologically similar to asbestos particles, were shown to induce severe proliferative ...reactions in the pleural mesothelium in a previous experiment carried out over 21 weeks. The present study aims to determine whether these fibers induce malignant mesotheliomas in rodents, and to examine chronic toxicity induced. Additionally, we investigated the specific differences observable between the biological responses to the direct infusion of the fibers alone into the pleural cavity and those induced by the co‐administration of the fibers with a known carcinogen. To detect the induction of malignant pleural mesotheliomas, two experiments were undertaken. In Experiment 1, four strains of mice, A/J, C3H, ICR, and C57BL, were examined for 52 weeks after experimental treatment with TISMO. In Experiment 2, the F344 rats were treated with TISMO alone, the lung carcinogen N‐bis (2‐hydroxypropyl) nitrosamine (DHPN) alone, both TISMO and DHPN, or left untreated and were then examined for 52 weeks. In this experiment, malignant lesion induction was expected in the co‐administration group. TISMO fibers were observed in the alveoli, indicating penetration through the visceral pleura in mice and rats. The histopathological detection of TISMO fibers in the liver and kidneys of mice and rats indicated migration of the fibers out of the pleural cavity. Atypical mesothelial cells with severe pleural proliferation were observed, but malignant mesotheliomas were not detected. Among the rats, there were no observed malignant alterations in the mesothelium induced by DHPN–TISMO co‐administration.
This study demonstrated that intra‐thoracic infusion of TISMO fiber did not cause malignant mesothelioma but did cause severe chronic inflammation and proliferation of pleural mesothelial cells in all strains of mice and rats.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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