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Journal of Toxicologic Pathology

Gabriel Siegel, Dan Regelman, Robert Maronpot, Moti Rosenstock, Shim-Mo Hayashi, Abraham Nyska
The demand for board certified toxicologic pathologists and expansion of IT capabilities has resulted in an increase of "virtual" and "distance" pathology (telepathology), and a need for greater flexibility in real time consultations. Newly developed microscope-integrated telepathology systems enable geographically remote stakeholders to view the live histopathology slide as seen by the microscope user. Simultaneous online viewing, annotation, and dialog between pathologists and study experts facilitates good science and economic benefits by enabling more timely and informed clinical decisions...
October 2018: Journal of Toxicologic Pathology
Ryota Tochinai, Kayoko Komatsu, Junta Murakami, Yuriko Nagata, Minoru Ando, Chie Hata, Tomo Suzuki, Shoichi Kado, Toshihide Kobayashi, Masayoshi Kuwahara
Cardiotoxicity is a concern in the development of microtubule-disassembling agents (MDAs) as vascular-disrupting agents of tumors. This study investigated cardiotoxicity in rats induced by a single-dose of combretastatin A4 disodium phosphate (CA4DP), an MDA and discussed the use of this rat model in nonclinical studies of MDAs. First, CA4DP (120 mg/kg) was administered to rats intravenously, and cardiac histopathology and blood biomarkers were examined after 0.5, 24, and 72 h. Next, CA4DP (120 mg/kg) was administered to rats intravenously, and the electrocardiography and echocardiography results were analyzed...
October 2018: Journal of Toxicologic Pathology
Hikaru Mitori, Takeshi Izawa, Mitsuru Kuwamura, Masahiro Matsumoto, Jyoji Yamate
In neonatal rats, glutamate could induce retinal thinning depending on the development stage, and the severity peaked at treatment on postnatal day (PND) 8. To elucidate the molecular mechanism of retinal thinning induced by L-glutamate in neonatal rats, we investigated the time-course gene expression profile in the developing retina in addition to initial histopathological changes. Histopathologically, apoptotic cells in the inner retina were observed at 6 hours after treatment on PNDs 4, 6 and 8, and inflammatory cell infiltration was noted at 24 hours...
October 2018: Journal of Toxicologic Pathology
Kiyotaka Nakano, Takashi Nishizawa, Daisuke Komura, Etsuko Fujii, Makoto Monnai, Atsuhiko Kato, Shin-Ichi Funahashi, Shumpei Ishikawa, Masami Suzuki
In xenograft models, orthotopic (ORT) engraftment is thought to provide a different tumor microenvironment compared with subcutaneous (SC) engraftment. We attempted to characterize the biological difference between OE19 (adenocarcinoma of the gastroesophageal junction) SC and ORT models by pathological analysis and CASTIN (CAncer-STromal INteractome) analysis, which is a novel method developed to analyze the tumor-stroma interactome framework. In SC models, SCID mice were inoculated subcutaneously with OE19 cells, and tumor tissues were sampled at 3 weeks...
October 2018: Journal of Toxicologic Pathology
Tomoyuki Saito, Yasufumi Toriniwa, Yukihito Ishii, Atsuhiro Uemura, Katsuhiro Miyajima, Kinuko Uno, Yuki Shirai, Dai Nakae, Takeshi Ohta
Metabolic diseases including nonalcoholic steatohepatitis develop due to various environmental factors. In particular, the westernization of food is closely related to the development of these diseases. In this study, we investigated pathophysiological changes in the livers of Zucker fatty (ZF) rats induced by feeding Western diets. Male ZF rats were fed a sucrose/fat/cholesterol-enriched diet (Western diet, WD) or standard diet (SD) for 18 weeks, from 7 to 25 weeks of age. Body weight, food intake, and biochemical parameters were periodically measured, histopathological analyses were performed at 25 weeks, and mRNA expression in the liver was determined...
October 2018: Journal of Toxicologic Pathology
Yuya Tsuchiya, Hiroki Sakai, Akihiro Hirata, Tokuma Yanai
Propolis is a resin-like material produced by honey bees from bud exudates and sap of plants and their own secretions. An ethanol extract of Brazilian green propolis (EEBGP) contains prenylated phenylpropanoids and flavonoids and has antioxidative and anti-inflammatory effects. Acetaminophen ( N -acetyl- p -aminophenol; APAP) is a typical hepatotoxic drug, and APAP-treated rats are widely used as a model of drug-induced liver injury. Oxidative stress and inflammatory reactions cause APAP-induced hepatocellular necrosis and are also related to expansion of the lesion...
October 2018: Journal of Toxicologic Pathology
Yuya Tsuchiya, Hiroki Sakai, Akihiro Hirata, Tokuma Yanai
It is well known that fasting substantially affects the metabolism of drugs and chemicals. Food restriction also affects drug kinetics, such as absorption, metabolism, and excretion, and therefore, it can potentially modulate the onset of chemical toxicity or drug-induced adverse reactions. In the present study, the expression of drug-metabolizing enzyme genes and total glutathione content in the liver, which are related to toxicity induced by overdose of the hepatotoxic drug acetaminophen ( N -acetyl- p -aminophenol; APAP), were examined in rats reared under different feeding conditions: ad libitum feeding, 16-h fasting, and food restriction (fed 70% of the average intake of ad libitum feeding for 10 days) conditions...
October 2018: Journal of Toxicologic Pathology
Shota Yoshida, Masanao Yokohira, Keiko Yamakawa, Yuko Nakano-Narusawa, Shohei Kanie, Nozomi Hashimoto, Katsumi Imaida
Ambroxol hydrochloride (AH) is an expectorant drug used to stimulate pulmonary surfactant and serous airway secretion. Surfactant proteins (SPs) are essential for maintaining respiratory structure and function, although SP expression has also been reported in lung inflammatory and proliferative lesions. To determine whether AH exerts modulatory effects on these lung lesions, we examined its effects on pleural thickening induced by intrathoracic administration of dipotassium titanate (TISMO) in A/JJmsSlc (A/J) mice...
October 2018: Journal of Toxicologic Pathology
Yoko Aniya
In research to develop healthy foods or preventive medicines from edible and medicinal herbs in Okinawa, we focused on the antioxidant activities of those bioresources. We first confirmed that the herbal antioxidant activities of such herbs increased upon ultraviolet irradiation treatment. This observation explains the high antioxidant activity of Okinawan vegetables, which grow under exposure to stronger ultraviolet light compared with those in other prefectures in Japan. Antidiabetic, hepatoprotective, cancer preventive, and cardioprotective actions were clarified using herbal extracts, and quercetin, chlorogenic acid, and gallic acid derivatives were isolated as antioxidant components from the herbs...
October 2018: Journal of Toxicologic Pathology
Masanao Yokohira, Keiko Yamakawa, Yuko Nakano-Narusawa, Nozomi Hashimoto, Shohei Kanie, Shota Yoshida, Katsumi Imaida
Surfactant proteins (SPs) are essential for the proper structure and respiratory function of the lungs. There are four subtypes of SPs: SP-A, SP-B, SP-C, and SP-D. The expectorant drug ambroxol hydrochloride is clinically used to stimulate pulmonary surfactant and airway serous secretion. In addition, previous studies showed that ambroxol regulated SP production and attenuated pulmonary inflammation, with ambroxol hydrochloride being found to suppress quartz-induced lung inflammation via stimulation of pulmonary surfactant and airway serous secretion...
October 2018: Journal of Toxicologic Pathology
Akane Kashimura, Kouji Tanaka, Hiroko Sato, Hidefumi Kaji, Masaharu Tanaka
To evaluate the usefulness of imaging mass spectrometry (IMS) technology for assessing drug toxicity, we analyzed animal tissues in an amiodarone (AMD)-induced phospholipidosis model by IMS and confirmed the relationship between the distribution of AMD, its metabolites, and representative phospholipids (phosphatidylcholine, PC) and histological changes. AMD was administered to rats for 7 days at 150 mg/kg/day. The lung, spleen, and mesenteric lymph node were histologically examined and analyzed using IMS. The detection intensities of AMD, its metabolites, and typical PCs were higher in regions infiltrated by foamy macrophages compared with normal areas...
July 2018: Journal of Toxicologic Pathology
Masaki Yamazaki, Nami Yabuki, Yasunori Suzuki, Mayumi Ito, Asuka Ikeda, Osamu Natori, Masami Suzuki, Atsuhiko Kato
Assessing how gene expression analysis by RNA sequencing (RNA-Seq) correlates to a unique morphology is increasingly necessary, and laser capture microdissection (LCM) is a critical research tool for discovering the genes responsible in a region of interest (ROI). Because RNA-Seq requires high-quality RNA, a sample preparation procedure that can preserve morphology and give the required quality of RNA is essential. A PAXgene®-fixed paraffin-embedded (XFPE) block can satisfy the need for high-quality RNA, but there are few reports on adapting the method for LCM, such as how small an ROI is analyzable by RNA-Seq...
July 2018: Journal of Toxicologic Pathology
Satoshi Matsuyama, Mohammad Rabiul Karim, Takeshi Izawa, Mitsuru Kuwamura, Jyoji Yamate
Macrophages are required during kidney development and appear in the initiation and propagation of renal injury. To establish baseline data, we analyzed the kinetics of the macrophage with different immunophenotypes in the developing rat kidney (fetus at 18 and 20 days, neonate at 1-21 days, and adult at 7-weeks old). Macrophages reacting to CD68, CD163, and MHC class II were identified in the cortex and medulla of the developing rat kidney. CD68+ macrophages appeared in the fetal kidney as early as fetal day 18, and the number increased gradually in the neonatal kidney, whereas MHC class II+ and CD163+ macrophages first appeared on neonatal days 4 and 8, respectively...
July 2018: Journal of Toxicologic Pathology
Masayo Miki, Norio Ohishi, Eiko Nakamura, Akane Furumi, Fukutaro Mizuhashi
To prevent fixation defects or artifacts in the whole bodies of fish caused by conventional fixatives, such as formalin solution, Bouin's fluid (BF), and Davidson's fluid (DF), the optimal fixatives and fixing method were examined. An improved method of fixing the whole bodies of fish was examined that makes use of a combination of 20% formalin and BF or DF. The fixatives were examined with four representative tissues, i.e., the gill, liver, intestinal tract, and kidney, to evaluate end points including the appearance of degraded tissues and artifacts caused by each fixative, overall morphological clarity of nuclei, staining intensity, and integrity of the other tissues...
July 2018: Journal of Toxicologic Pathology
Vittoria Castiglioni, Enrico Radaelli
Murine hepatoblastoma (HB) is a rare spontaneous tumor with controversial histogenesis. It mainly occurs in aged males, frequently in close association with preexisting hepatocellular neoplasms. The present work describes a spontaneous HB arising within a hepatocellular carcinoma (HCC) in a 22-month-old male C57BL/6J mouse. The mouse also developed pulmonary co-metastases with either tumor components physically associated within the same metastatic foci. Microscopically, the HB consisted of a densely cellular neoplastic growth composed of palisades and perivascular pseudorosettes of poorly differentiated primitive cells, with a scant amount of cytoplasm, elongated hyperchromatic nuclei, and a high mitotic rate, whereas the hepatocellular carcinoma was composed of solid areas of neoplastic hepatocytes...
July 2018: Journal of Toxicologic Pathology
Ayumi Eguchi, Mari Inohana, Misato Nakamura, Rei Nagahara, Megu Itahashi, Kota Nakajima, Toshinori Yoshida, Makoto Shibutani
A 3-year-old female Richardson's ground squirrel developed a subcutaneous mass at the left oral angle. Seven days after removal of the mass, the mass recurred and metastasized to the cervical lymph node. Histologically, the primary mass was subdivided by fibrous trabeculae into various-sized neoplastic cell lobules showing a solid growth pattern with frequent mitoses and sometimes forming intracytoplasmic lumina. Large to medium-sized lobules formed a central cyst plugged by comedo necrosis. Neoplastic cells showed infiltrative subcutaneous growth...
July 2018: Journal of Toxicologic Pathology
Takuma Tsuchiya, Aki Kijima, Yuji Ishii, Shinji Takasu, Yuh Yokoo, Akiyoshi Nishikawa, Tokuma Yanai, Takashi Umemura
Oxidative stress is well known as a key factor of chemical carcinogenesis. However, the actual role of oxidative stress in carcinogenesis, such as oxidative stress-related in vivo mutagenicity, remains unclear. It has been reported that 8-hydroxydeoxyguanosine (8-OHdG), an oxidized DNA lesion, might contribute to chemical carcinogenesis. Potassium bromate (KBrO3 ) and nitrofurantoin (NFT) are known as renal carcinogens in rats. Our previous studies showed an increase in mutant frequencies accompanied by an increased level of 8-OHdG in the kidneys of rodents following KBrO3 or NFT exposure...
July 2018: Journal of Toxicologic Pathology
Takuma Tsuchiya, Aki Kijima, Yuji Ishii, Shinji Takasu, Yuh Yokoo, Akiyoshi Nishikawa, Tokuma Yanai, Takashi Umemura
Despite its antimicrobial activity, nitrofurantoin (NFT) is a renal carcinogen in rats. Oxidative stress induced by reduction of the nitro group of NFT may contribute to its genotoxicity. This is supported by our recent results indicating that the structure of the nitrofuran plays a key role in NFT-induced genotoxicity, and oxidative DNA damage is involved in renal carcinogenesis. Nuclear factor erythroid 2-related factor 2 (NRF2) regulates cellular responses to oxidative stress. To clarify the role of oxidative stress in the chemical structure-related genotoxic mechanism of NFT, we performed reporter gene mutation assays for NFT and 5-nitro-2-furaldehyde (NFA) using Nrf2 -proficient and Nrf2 -deficient gpt delta mice...
July 2018: Journal of Toxicologic Pathology
Jane Tey Xin Ying, Masanao Yokohira, Yuko Nakano-Narusawa, Keiko Yamakawa, Nozomi Hashimoto, Katsumi Imaida
It is known that γH2AX, which is formed when there is a double-strand break in DNA, can act as a sensitive marker of genomic instability. In this experiment, the time-course manner of the expression of γH2AX in the lung was examined in the early phase after treatment with a lung carcinogen, N-bis (2-hydroxypropyl) nitrosamine (DHPN). The expression of γH2AX is expected to be one of the useful markers for lung carcinogenesis in early stages. Rats were separated into 10 groups of 5 rats. The DHPN groups were administered 0...
July 2018: Journal of Toxicologic Pathology
Robert R Maronpot, Cheryl A Hobbs, Shim-Mo Hayashi
When a comet assay, an increasingly popular in vivo genotoxicity test, shows a positive test result, interpretation of that response requires ruling out any confounding tissue site toxicity. Since the comet assay typically uses only two or three daily doses of test agent, precursor tissue changes indicative of toxicity may be easily overlooked. Using case examples for two flavoring agents, perillaldehyde and 4,5-epoxydec-2( trans )-enal, we highlight the role of pathology peer review in verifying precursor tissue changes indicative of tissue site toxicity, thereby increasing confidence in final interpretation of comet assay results...
July 2018: Journal of Toxicologic Pathology
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