Self-organization, quality control, and preclinical studies of human iPSC-derived retinal sheets for tissue-transplantation therapy.

Three-dimensional retinal organoids (3D-retinas) are a promising graft source for transplantation therapy. We previously developed self-organizing culture for 3D-retina generation from human pluripotent stem cells (hPSCs). Here we present a quality control method and preclinical studies for tissue-sheet transplantation.

Effects of microsampling on toxicity assessment of hematotoxic compounds in a general toxicity study in rats.

Microsampling (MS) has been increasingly used in toxicity studies reducing animal use for toxicokinetic analysis. However, especially for drugs with hematotoxic properties, the potential effects of MS on hematological parameters and subsequent toxicity assessment should be considered, while such properties are frequently unknown at the discovery stage. Here, we conducted a rat 2-week study of hematotoxic compounds and evaluated the effects of MS on toxicity assessment.

Spontaneous membranoproliferative glomerulonephritis in a young Crl:CD-1(ICR) mouse.

Here, we reported a spontaneous case of membranoproliferative glomerulonephritis observed in a young ICR mouse. A 5-week-old female mouse was euthanized owing to abdominal swelling and increased body weight. At necropsy, generalized subcutaneous edema, and clear, colorless, non-viscous ascites were observed.

Dose- and time-dependent changes in blood and adrenal levels of multiple steroids in rats after administration of ketoconazole with or without ACTH.

To verify simultaneous measurement of blood levels of adrenal steroids as a tool to evaluate drug effects on adrenal steroidogenesis, dose- and time-dependent changes in blood levels of corticosterone and its precursors (pregnenolone, progesterone and deoxycorticosterone), as well as their relationship with the pathological changes in the adrenal gland, were examined in rats dosed with ketoconazole (KET). Also examined were whether effects on adrenal steroidogenesis that were not obvious in the blood steroid levels after sole administration of KET could be revealed by post-administration of ACTH, and the correlation between the blood and adrenal steroid levels. Male rats were dosed with 15, 50, or 150 mg/kg of KET for 1 or 7 days with or without ACTH, and the blood and adrenal concentrations of the steroids were measured.

Physiological and drug-induced changes in blood levels of adrenal steroids and their precursors in cynomolgus monkeys: An application of steroid profiling by LC-MS/MS for evaluation of the adrenal toxicity.

The adrenal gland is the most common toxicological target of drugs within the endocrine system, and inhibition of adrenal steroidogenesis can be fatal in humans. However, methods to evaluate the adrenal toxicity are limited. The aim of the present study was to verify the usefulness of simultaneous measurement of blood levels of multiple adrenal steroids, including precursors, as a method to evaluate drug effects on adrenal steroidogenesis in cynomolgus monkeys.

Usefulness of Simultaneous Measurement of Plasma Steroids, Including Precursors, for the Evaluation of Drug Effects on Adrenal Steroidogenesis in Rats.

The aim of this study was to evaluate the usefulness of simultaneous measurement of plasma steroids, including precursors, for the evaluation of drug effects on adrenal steroidogenesis in vivo. Plasma concentrations of corticosterone and its precursors were examined in rats dosed with compounds that affect adrenal steroidogenesis via different modes of action as well as the relationships of the changes with blood chemistry and adrenal histopathology. Male rats were dosed with tricresyl phosphate, aminoglutethimide, trilostane (TRL), metyrapone (MET), ketoconazole (KET), or mifepristone for 7 days.

MicroRNA-mediated Th2 bias in methimazole-induced acute liver injury in mice.

MicroRNA (miRNA) is a class of small non-coding RNAs containing approximately 20 nucleotides that negatively regulate target gene expression. Little is known about the role of individual miRNAs and their targets in immune- and inflammation-related responses in drug-induced liver injury. In the present study, involvement of miRNAs in the T helper (Th) 2-type immune response was investigated using a methimazole (MTZ)-induced liver injury mouse model.

Histopathological characteristics of renal changes in human renin-angiotensinogen double transgenic rats.

The human renin-angiotensinogen double transgenic rat (dTGR) is a model of hypertension. The aim of this short report was to describe the histopathological characteristics of the renal changes in this rat strain in detail. Seven to nine-week-old male dTGRs were euthanized, and their kidneys were histopathologically examined.

Changes in plasma concentrations of corticosterone and its precursors after ketoconazole administration in rats: An application of simultaneous measurement of multiple steroids using LC-MS/MS.

The adrenal gland is the most common toxicological target in the endocrine system, and inhibition of adrenal steroidogenesis by drugs can be fatal in humans. However, methods to evaluate the drug effect are limited. Recently, simultaneous measurement of multiple steroids, including precursors, has become possible.

Glomerulonephritis in a ferret with feline coronavirus infection.

A male domestic ferret (Mustela putorius furo), which was purchased from outside of Japan at 13 weeks of age, was euthanized at 18 months of age because of poor health. At autopsy, the liver, spleen, and mesenteric lymph node were enlarged, and white foci were observed on the outer surface of the liver. The outer surface of the mesenteric lymph node was dark red.

Proceedings of the 2013 Joint JSTP/NTP Satellite Symposium.

The first joint Japanese Society of Toxicologic Pathology (JSTP) and National Toxicology Program (NTP) Satellite Symposium, entitled "Pathology Potpourri," was held on January 29(th) at Okura Frontier Hotel in Tsukuba, Ibaraki, Japan, in advance of the JSTP's 29(th) Annual Meeting. The goal of this Symposium was to present current diagnostic pathology or nomenclature issues to the toxicologic pathology community. This article presents summaries of the speakers' presentations, including diagnostic or nomenclature issues that were presented, select images that were used for audience voting or discussion, and the voting results.

Spontaneous Rhabdomyosarcoma in a Common Marmoset ( Callithrix jacchus ).

The common marmoset (Callithrix jacchus) is now widely used in various research fields, including toxicology. However, information about the background pathology of this species is scarce. Here, we report a case of rhabdomyosarcoma that spontaneously occurred in a common marmoset.

Cystic cholangioma in the thoracic cavity of a rat.

A female congenic rat produced by repeated backcrossing of Nihon rats, a model for hereditary renal cell carcinoma, to Brown Norway rats was necropsied at 24 months of age. At necropsy, a white mass about 1 centimeter in size was observed in the thoracic cavity, and the mass partly adhered to the esophagus and the diaphragm. Histologically, the mass was clearly circumscribed by connective tissue, and consisted of neoplastic cuboidal epithelial cells that showed cystic tubular proliferation.

Immunohistochemical and ultrastructural analyses of cytoplasmic blood plasma inclusions of rat hepatocytes.

In the present study, we investigated the histological, immunohistochemical and ultrastructural characteristics of cytoplasmic blood plasma inclusions that spontaneously occurred in a rat liver. Histologically, a number of cytoplasmic inclusions were observed in the liver of an 8-week-old female SD rat. These inclusions were strongly positive for PAS staining and resistant to diastase digestion.

Spontaneous fibrosarcoma with pleomorphic appearance in an aged brown norway rat.

An 18-month-old male Brown Norway (BN) rat showed a grayish-white subcutaneous mass in the right cheek. Histologically, the mass was composed of highly pleomorphic cells producing collagen. Immunohistochemical analysis showed that the tumor cells were strongly positive for vimentin and partially positive for Ki-67; however, they were negative for ED-1, ED-2, S-100, cytokeratin, desmin and myoglobin.

Hyaline glomerulopathy with tubulo-fibrillary deposits in young ddY mice.

Hyaline glomerulopathy with tubulo-fibrillary deposits was observed in two young female ddY mice. One of the mice showed gross systemic edema and bilateral enlargement and pale color of the kidneys, whereas no significant gross findings were noted in the other mouse. Microscopically, a large number of the glomeruli in both mice were enlarged because of diffuse and global deposition of amorphous eosinophilic materials.

5-azacytidine, a chemotherapeutic drug, induces TRAIL-mediated apoptosis in mouse thymocytes in vivo.

5-azacytidine (5AzC) is a cytidine analogue with two main effects on cellular conditions; DNA damage, resulting in apoptosis, and DNA hypomethylation, restoring normal growth control and differentiation. However, the molecular mechanism of 5AzC-induced apoptosis is not fully understood. The aim of the present study is to clarify this mechanism in mouse thymocytes in vivo.

Spontaneous cutaneous mast cell tumor with lymph node metastasis in a Richardson's ground squirrel (Spermophilus richardsonii).

A 4-year-old female Richardson's ground squirrel (Spermophilus richardsonii) presented with multicentric nodules arising from the skin of the middle of the tail and lumbosacral regions. Histologically, the nodules were composed of a proliferation of spindloid to pleomorphic cells that sometimes formed sheets and fascicular to storiform patterns. Diffuse infiltration of eosinophils was also noted.