GLUTATHIONE S-TRANSFERASE PLACENTAL FORM IS A MARKER FOR BILE DUCT CARCINOMA, BUT NOT HEPATOCELLULAR CARCINOMA, IN HUMANS.

Immunohistochemical studies using anti-human glutathione S-transferase placental form (GST-π) rabbit antibody were carried out to investigate various hepatobiliary diseases in humans. Hepatocytes in fetal and adult liver without disease were negatively or positively stained while intra-or extrahepatic bile duct epithelial cells were positively or strongly positively stained with GST-π. Hepatocytes in regenerated nodules in liver cirrhosis were positively stained. Hepatocellular carcinomas were not strongly positively stained, while cholangiocarcinomas and cancers of the biliary tract were positively or strongly positively stained. These results indicate that GST-π staining is a useful marker for the diagnosis of intra-or extra-hepatic bile duct carcinomas in humans, and that enzyme activity is not phenotypically expressed in hepatocellular carcinomas

Carcinogen-induced Thyroid Proliferative Lesions in Wistar Hannover GALAS Rats with Thyroid Dysplasia

Incidences and morphological features of thyroid proliferative lesions induced by carcinogens in Wistar Hannover GALAS rats (GALAS rats) showing normal growth with or without thyroid dysplasia were examined. All thyroid tissue samples were obtained from our recently conducted study using male GALAS rats treated with 5 carcinogens according to the medium-term multiorgan carcinogenicity bioassay protocol (called DMBDD treatment). In the DMBDD-treated rats, thyroid dysplasia was found in 9 out of 114 rats. Follicular cell adenomas were found in 5 out of 9 rats with thyroid dysplasia and in 7 out of 105 rats without thyroid dysplasia. The incidence of adenoma was significantly increased in rats with thyroid dysplasia (55.6%) compared with that in rats without thyroid dysplasia (6.7%). Adenomas in rats with thyroid dysplasia were observed as single or multiple nodules, well demarcated and composed of variously sized vacuolated cells or unvacuolated cells. These histopathological features and staining profiles of luminal colloid for PAS and thyroglobulin, together with PCNA-positive cells, were fundamentally similar to those of rats without thyroid dysplasia. On the other hand, the luminal colloid in adenomas of rats with thyroid dysplasia had a tendency to be poorly stained for T4 compared with that of rats without thyroid dysplasia. From these findings, it appears that dysplastic thyroids of rats showing normal growth are more sensitive to carcinogens than normal thyroids. In addition, the morphological features of carcinogen-induced thyroid proliferative lesions in GALAS rats with thyroid dysplasia were fundamentally similar to those of rats without thyroid dysplasia, except for the vacuoles and T4 staining profile

Absence of in vivo mutagenicity of multi-walled carbon nanotubes in single intratracheal instillation study using F344 gpt delta rats

Abstract Introduction It is known that fibrous particles of micrometer length, such as carbon nanotubes, which have same dimensions as asbestos, are carcinogenic. Carcinogenicity of nanomaterials is strongly related to inflammatory reactions; however, the genotoxicity mechanism(s) is unclear. Indeed, inconsistent results on genotoxicity of multi-walled carbon nanotubes (MWCNTs) have been shown in several reports. Therefore, we analyzed the in vivo genotoxicity induced by an intratracheal instillation of straight MWCNTs in rats using a different test system\u2014the Pig-a gene mutation assay\u2014that can reflect the genotoxicity occurring in the bone marrow. Since lungs were directly exposed to MWCNTs upon intratracheal instillation, we also performed the gpt assay using the lungs. Findings We detected no significant differences in Pig-a mutant frequencies (MFs) between the MWCNT-treated and control rats. Additionally, we detected no significant differences in gpt MFs in the lung between the MWCNT-treated and control rats. Conclusions Our findings indicated that a single intratracheal instillation of MWCNTs was non-mutagenic to both the bone marrow and lung of rats

Empirical Data Confirm Autism Symptoms Related to Aluminum and Acetaminophen Exposure

Autism is a condition characterized by impaired cognitive and social skills, associated with compromised immune function. The incidence is alarmingly on the rise, and environmental factors are increasingly suspected to play a role. This paper investigates word frequency patterns in the U.S. CDC Vaccine Adverse Events Reporting System (VAERS) database. Our results provide strong evidence supporting a link between autism and the aluminum in vaccines. A literature review showing toxicity of aluminum in human physiology offers further support. Mentions of autism in VAERS increased steadily at the end of the last century, during a period when mercury was being phased out, while aluminum adjuvant burden was being increased. Using standard log-likelihood ratio techniques, we identify several signs and symptoms that are significantly more prevalent in vaccine reports after 2000, including cellulitis, seizure, depression, fatigue, pain and death, which are also significantly associated with aluminum-containing vaccines. We propose that children with the autism diagnosis are especially vulnerable to toxic metals such as aluminum and mercury due to insufficient serum sulfate and glutathione. A strong correlation between autism and the MMR (Measles, Mumps, Rubella) vaccine is also observed, which may be partially explained via an increased sensitivity to acetaminophen administered to control fever

A 90-day Feeding Toxicity Study of l-Serine in Male and Female Fischer 344 Rats

A subchronic feeding study of l-serine (l-Ser) was conducted with groups of 10 male and 10 female Fischer 344 rats fed a powder diet containing 0, 0.06, 0.5, 1.5 or 5.0% concentrations of l-Ser for 90 days. There were no toxicologically significant, treatment-related changes with regards to body weight, food intake, water intake or urinalysis data. In several of the hematology, serum biochemistry and organ weight parameters, significant changes were observed between some of the treated groups and the controls. All these changes, however, were subtle and lacked any corresponding pathological findings. In addition, the increased or decreased values remained within the range of the historical control values. In fact, histopathological assessment revealed only sporadic and/or spontaneous lesions. In conclusion, the no-observed-adverse-effect-level (NOAEL) for l-Ser was, therefore, determined to be at least a dietary dose of 5.0% (2765.0 mg/kg body weight/day for males and 2905.1 mg/kg body weight/day for females) under the present experimental conditions

Interleukin-17 Contributes to the Pathogenesis of Autoimmune Hepatitis through Inducing Hepatic Interleukin-6 Expression

T helper cells that produce IL-17 (Th17 cells) have recently been identified as the third distinct subset of effector T cells. Emerging data suggests that Th17 cells play an important role in the pathogenesis of many liver diseases by regulating innate immunity, adaptive immunity, and autoimmunity. In this study, we examine the role and mechanism of Th17 cells in the pathogenesis of autoimmune hepatitis (AIH). The serum levels of IL-17 and IL-23, as well as the frequency of IL-17+ cells in the liver, were significantly elevated in patients with AIH, compared to other chronic hepatitis and healthy controls. The hepatic expressions of IL-17, IL-23, ROR-γt, IL-6 and IL-1β in patients with AIH were also significantly increased and were associated with increased inflammation and fibrosis. IL-17 induces IL-6 expression via the MAPK signaling pathway in hepatocytes, which, in turn, may further stimulate Th17 cells and forms a positive feedback loop. In conclusion, Th17 cells are key effector T cells that regulate the pathogenesis of AIH, via induction of MAPK dependent hepatic IL-6 expression. Blocking the signaling pathway and interrupting the positive feedback loop are potential therapeutic targets for autoimmune hepatitis

Distinct transcriptional regulatory modules underlie STAT3's cell type-independent and cell type-specific functions

Transcription factors (TFs) regulate gene expression by binding to short DNA sequence motifs, yet their binding specificities alone cannot explain how certain TFs drive a diversity of biological processes. In order to investigate the factors that control the functions of the pleiotropic TF STAT3, we studied its genome-wide binding patterns in four different cell types: embryonic stem cells, CD4+ T cells, macrophages and AtT-20 cells. We describe for the first time two distinct modes of STAT3 binding. First, a small cell type-independent mode represented by a set of 35 evolutionarily conserved STAT3-binding sites that collectively regulate STAT3's own functions and cell growth. We show that STAT3 is recruited to sites with E2F1 already pre-bound before STAT3 activation. Second, a series of different transcriptional regulatory modules (TRMs) assemble around STAT3 to drive distinct transcriptional programs in the four cell types. These modules recognize cell type-specific binding sites and are associated with factors particular to each cell type. Our study illustrates the versatility of STAT3 to regulate both universal- and cell type-specific functions by means of distinct TRMs, a mechanism that might be common to other pleiotropic TFs. © The Author(s) 2013. Published by Oxford University Press.Link_to_subscribed_fulltex