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Mouse Models for Cancer Stem Cell Research.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The cancer stem cell concept assumes that cancers are mainly sustained by a small pool of neoplastic cells, known as cancer stem cells or tumor initiating cells, which are able to reproduce themselves and produce phenotypically heterogeneous cells with lesser tumorigenic potential. Cancer stem cells represent an appealing target for development of more selective and efficient therapies. However, direct testing of the cancer stem cell concept and assessment of its therapeutic implications in human cancers have been complicated by the use of immunocompromised mice. Genetically defined immunocompetent autochthonous mouse ...
Source: Toxicologic Pathology - November 17, 2009 Category: Pathology Authors: Cheng L, Ramesh AV, Flesken-Nikitin A, Choi J, Nikitin AY Tags: Toxicol Pathol Source Type: journals

Alternative Mouse Models for Carcinogenicity Assessment: Industry Use and Issues With Pathology Interpretation.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The Carcinogenicity Alternative Mouse Models (CAMM) Working Group of the Society of Toxicologic Pathology (STP) surveyed the membership to define current practices and opinions in industry regarding the use of alternative mouse models for carcinogenicity testing. The results of the survey indicated that CAMM are used most often to fulfill a regulatory requirement (e.g., to replace the two-year mouse bioassay) and are being accepted by regulatory agencies. Alternative models are also sometimes used for internal decision making or to address a mechanistic question. The CAMM most commonly used are the p53+/- and rasH2. Th...
Source: Toxicologic Pathology - November 13, 2009 Category: Pathology Authors: Long GG, Morton D, Peters T, Short B, Skydsgaard M Tags: Toxicol Pathol Source Type: journals

Safety Assessment Considerations and Strategies for Targeted Small Molecule Cancer Therapeutics in Drug Discovery.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
This article presents concepts and strategies to reduce the attrition of small molecule oncology therapeutic drug candidates due to toxicity. PMID: 19907054 [PubMed - as supplied by publisher] (Source: Toxicologic Pathology)
Source: Toxicologic Pathology - November 11, 2009 Category: Pathology Authors: Westhouse RA Tags: Toxicol Pathol Source Type: journals

An Industry Perspective on the Utility of Short-Term Carcinogenicity Testing in Transgenic Mice in Pharmaceutical Development.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
International guidelines allow for use of a short-term cancer bioassay (twenty-six weeks) in transgenic mice as a substitute for one of the two required long-term rodent bioassays in the preclinical safety evaluation of pharmaceuticals. The two models that have gained the widest acceptance by sponsors and regulatory authorities are the CB6F1-RasH2 mouse hemizygous for a human H-ras transgene and the B6.129N5-Trp53 mouse heterozygous for a p53 null allele. The p53(+/-) model is of particular value for compounds with residual concern that genotoxic activity may contribute to tumorigenesis. The rasH2 model is an appropria...
Source: Toxicologic Pathology - November 5, 2009 Category: Pathology Authors: Storer RD, Sistare FD, Reddy MV, Degeorge JJ Tags: Toxicol Pathol Source Type: journals

Cancer Risk Assessment Approaches at the FDA/CDER: Is the Era of the 2-Year Bioassay Drawing to a Close?Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Determining the carcinogenic potential of materials to which humans have significant exposures is an important, complex, and imperfect exercise. Not only are the methods for such determinations protracted and expensive and use large numbers of animals, extrapolation of data from such studies to human risk is imprecise. With improved understanding of oncogene activation and tumor suppressor gene inactivation, a number of animal models have been developed to dramatically reduce latency for chemically induced cancers and has led to the development and use of shorter carcinogenicity assays. Recent studies by a number of in...
Source: Toxicologic Pathology - November 3, 2009 Category: Pathology Authors: Jacobson-Kram D Tags: Toxicol Pathol Source Type: journals

Panel Discussion: Alternative Mouse Models for Carcinogenicity Assessment.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
This article summarizes key points from Dr. Bernard Leblanc's presentation European Perspectives on Alternative Mouse Carcinogenicity Models and a distillation of questions and answers from a panel discussion following presentations on Alternative Mouse Models for Carcinogenicity Assessment at the Society of Toxicologic Pathology's annual symposium on June 23, 2009, in Washington, DC. PMID: 19884653 [PubMed - as supplied by publisher] (Source: Toxicologic Pathology)
Source: Toxicologic Pathology - November 2, 2009 Category: Pathology Authors: French J, Leblanc B, Long G, Morton D, Storer R, Leighton J, Swenberg J, Tsuda H Tags: Toxicol Pathol Source Type: journals

Unintended Effects of Cranial Irradiation on Cognitive Function.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
This review summarizes some of the topics discussed at the 28th Annual Symposium of the Society of Toxicologic Pathology. The symposium was held in Washington, DC, in 2009 and dealt with unintended adverse events associated with cranial irradiation as part of cancer therapy. We will discuss the importance of considering genetic susceptibility and sex differences in susceptibility to develop these adverse events. Further, we will discuss potential mechanisms contributing to these events, including alterations in neurogenesis and increased oxidative stress following irradiation and potential alterations in synaptic and d...
Source: Toxicologic Pathology - October 30, 2009 Category: Pathology Authors: Raber J Tags: Toxicol Pathol Source Type: journals

Unintended Hepatic Adverse Events Associated with Cancer Chemotherapy.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Chemotherapy is meant to be toxic, but it is particularly aimed at the tumor cells. Collateral damage may occur to normal cells and tissues, especially if they are fairly rapidly regenerating, as is the case for bone marrow cells, intestinal epithelial cells, and liver cells after hepatic injury. The liver has a great capacity to resist injury, overcome it, and to regenerate, even after quite massive injury (resection of 50%-65%, for example). This capacity may make it susceptible to chemotherapeutic toxicity, and a struggle between injury and adaptation, leading to recovery and tolerance or to failure and death. If th...
Source: Toxicologic Pathology - October 26, 2009 Category: Pathology Authors: Senior JR Tags: Toxicol Pathol Source Type: journals

Assessment of the Toxicity of Hydralazine in the Rat Using an Ultrasensitive Flow-based Cardiac Troponin I Immunoassay.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
In conclusion, the increases in cTnI concentrations six hours after the administration of hydralazine were indicative of a myocardial damage that did not consistently have a microscopic correlate. However, the window of increased cTnI concentrations was short, and only microscopic evaluation of the heart detected the damage at twenty-four to forty-eight hours after the episode of acute myocardial necrosis. PMID: 19854888 [PubMed - as supplied by publisher] (Source: Toxicologic Pathology)
Source: Toxicologic Pathology - October 23, 2009 Category: Pathology Authors: Mikaelian I, Coluccio D, Hirkaler GM, Downing JC, Rasmussen E, Todd J, Estis J, Lu QA, Nicklaus R Tags: Toxicol Pathol Source Type: journals

A Review of the Molecular Mechanisms of Chemically Induced Neoplasia in Rat and Mouse Models in National Toxicology Program Bioassays and Their Relevance to Human Cancer.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Tumor response in the B6C3F1 mouse, F344 rat, and other animal models following exposure to various compounds provides evidence that people exposed to these or similar compounds may be at risk for developing cancer. Although tumors in rodents and humans are often morphologically similar, underlying mechanisms of tumorigenesis are often unknown and may be different between the species. Therefore, the relevance of an animal tumor response to human health would be better determined if the molecular pathogenesis were understood. The underlying molecular mechanisms leading to carcinogenesis are complex and involve multiple ...
Source: Toxicologic Pathology - October 20, 2009 Category: Pathology Authors: Hoenerhoff MJ, Hong HH, Ton TV, Lahousse SA, Sills RC Tags: Toxicol Pathol Source Type: journals

The Roles of the Toxicologic Pathologist in Cancer Research.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Cancer in an important disease throughout the world and a major cause of death in both humans and animals. Pathologists play a critical role in cancer research and in the diagnosis, treatment, and prevention of human and animal cancers. They participate in basic and translational research in laboratories of colleges and universities, other research institutes, government research and regulatory agencies, and in the biotech, chemical, and pharmaceutical industries. This introductory review to the 2009 STP Symposium on Cancer will identify and discuss the major roles of pathologists in cancer research. PMID: 19843952...
Source: Toxicologic Pathology - October 19, 2009 Category: Pathology Authors: Ward JM Tags: Toxicol Pathol Source Type: journals

Reproductive Lesions in Female Harlan Sprague-Dawley Rats Following two-Year Oral Treatment With Dioxin and Dioxin-Like Compounds.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Results from previously published animal studies suggest that prenatal and postnatal exposure to dioxin and dioxin-like compounds (DLCs) may profoundly affect the reproductive system of both sexes via endocrine disruption. In the present work, we evaluate the toxicity and carcinogenicity of various DLCs, with an emphasis on their effect on the reproductive organs, induced by chronic exposure of female adult Harlan Sprague-Dawley rats. This investigation represents part of an initiative of the National Toxicology Program to determine the relative potency of chronic toxicity and carcinogenicity of polychlorinated dioxins...
Source: Toxicologic Pathology - October 19, 2009 Category: Pathology Authors: Yoshizawa K, Brix AE, Sells DM, Jokinen MP, Wyde M, Orzech DP, Kissling GE, Walker NJ, Nyska A Tags: Toxicol Pathol Source Type: journals

Global Gene Expression Profiling of Hyperkeratotic Skin Lesions from Inner Mongolians Chronically Exposed to Arsenic.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The skin is an organ that is highly sensitive to chronic arsenic (As) exposure. Skin lesions such as hyperkeratoses (HKs) are common early manifestations of arsenicosis in humans. HKs can be precursor lesions of nonmelanoma skin cancers (NMSCs), but the driving forces behind their formation and how they may ultimately progress to NMSCs are unknown. The goal of this study was to examine the global gene expression profiles of As-related HKs in an effort to better understand gene expression changes that are potentially associated with early stages of As carcinogenesis. HK biopsies were removed from individuals living in a...
Source: Toxicologic Pathology - October 18, 2009 Category: Pathology Authors: Bailey K, Xia Y, Ward WO, Knapp G, Mo J, Mumford JL, Owen RD, Thai SF Tags: Toxicol Pathol Source Type: journals

Dietary Fat-Influenced Development of Colon Neoplasia in ApcMin Mouse Exposed to Benzo(a)pyrene.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The objective of this study was to investigate whether the formation of colon tumors in adult Apc(Min) mice was influenced by the ingestion of different types of fat containing benzo(a)pyrene [B(a)P], a polycyclic aromatic hydrocarbon compound. Treatment consisted of 50 and 100 microg B(a)P/kg body weight dissolved in peanut or coconut oil (representatives of unsaturated and saturated fats, respectively) administered daily to six-week-old male Apc(Min) mice via oral gavage for sixty days. At the end of exposure, mice were sacrificed; jejunum and colons were retrieved and preserved in 10% formalin for observation for gross ...
Source: Toxicologic Pathology - October 18, 2009 Category: Pathology Authors: Harris DL, Washington MK, Hood DB, Jackson Roberts L, Ramesh A Tags: Toxicol Pathol Source Type: journals

Differential Effects of 17B -Estradiol and of Synthetic Progestins on Aldosterone-Salt Induced Kidney Disease.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Conclusion: The choice of specific synthetic progestins has profound implications on the development of kidney injury and renal gene expression under conditions of elevated aldosterone serum levels and salt intake. PMID: 19841131 [PubMed - as supplied by publisher] (Source: Toxicologic Pathology)
Source: Toxicologic Pathology - October 18, 2009 Category: Pathology Authors: Arias-Loza PA, Muehlfelder M, Elmore SA, Maronpot R, Hu K, Blode H, Hegele-Hartung C, Fritzemeier KH, Ertl G, Pelzer T Tags: Toxicol Pathol Source Type: journals

Potassium Bromate Enhances N-Ethyl-N-Hydroxyethylnitrosamine-Induced Kidney Carcinogenesis Only at High Doses in Wistar Rats: Indication of the Existence of an Enhancement Threshold.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
As susceptibility to carcinogens varies considerably among different strains of experimental animals, evaluation of dose-response relationships for genotoxic carcinogen in different strains is indispensable for risk assessment. Potassium bromate (KBrO3) is a genotoxic carcinogen inducing kidney cancers at high doses in male F344 rats, but little is known about its carcinogenic effects in other strains of rats. The purpose of the present study was to determine dose-response relationships for carcinogenic effects of KBrO3 on N-ethyl-N-hydroxyethylnitrosamine (EHEN)-induced kidney carcinogenesis in male Wistar rats. We fo...
Source: Toxicologic Pathology - October 14, 2009 Category: Pathology Authors: Wei M, Hamoud AS, Yamaguchi T, Kakehashi A, Morimura K, Doi K, Kushida M, Kitano M, Wanibuchi H, Fukushima S Tags: Toxicol Pathol Source Type: journals

Phospholipidosis in Neurons Caused by Posaconazole, without Evidence for Functional Neurologic Effects.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The azole antifungal drug posaconazole caused phospholipidosis in neurons of the central nervous system, dorsal root ganglia of the spinal cord, and myenteric plexus in chronic toxicity studies in dogs. The time of onset, light and electron microscopic features, neurologic and electrophysiologic effects on the central and peripheral nervous systems, and potential for regression were investigated in a series of studies with a duration of up to one year. Nuclei of the medulla oblongata were the prominently affected areas of the brain. Neurons contained cytoplasmic vacuoles with concentrically whorled plasma membrane-like...
Source: Toxicologic Pathology - October 14, 2009 Category: Pathology Authors: Cartwright ME, Petruska J, Arezzo J, Frank D, Litwak M, Morrissey RE, Macdonald J, Davis TE Tags: Toxicol Pathol Source Type: journals

STP Debate on the Desirability of an International Mechanism for Recognizing Qualified Toxicologic Pathologists.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The June 2009 Town Hall meeting of the Society of Toxicologic Pathology (STP) and a subsequent survey considered whether or not STP should endorse a published proposal (Toxicol Pathol 37: 553-561, 2009) by the International Federation of Societies of Toxicologic Pathologists (IFSTP) to provide global recognition by credential review for toxicologic pathologists engaged in regulatory-type, nonclinical toxicology studies. One-third (374 of 1082) of STP members answered the survey. The majority of respondents rejected the IFSTP proposal (55% against) but favored the concept of global recognition (57% for), if available to...
Source: Toxicologic Pathology - October 8, 2009 Category: Pathology Authors: Bolon B, Ochoa R, Mann P Tags: Toxicol Pathol Source Type: journals

Time-course Study of the Immunotoxic Effects of the Anticancer Drug Chlorambucil in the Rat.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
In 2005, the International conference on harmonization (ICH) recommended that all new human pharmaceuticals be tested for unintended immunomodulatory potential via a tiered approach. Included in this approach is a semiquantitative description of changes in the separate compartments of lymphoid tissue (also called enhanced histopathology). Chlorambucil was administered to Hanover Wistar rats at regular time points, followed by a treatment-free (recovery) period. Groups of treated and control animals were sacrificed regularly during both the treatment and recovery periods. Selected tissues were removed, weighed fresh and...
Source: Toxicologic Pathology - October 4, 2009 Category: Pathology Authors: Pearse G, Pietersma A, Cunliffe J, Foster JR, Turton J, Derbyshire N, Randall KJ Tags: Toxicol Pathol Source Type: journals

Evaluation of Subchronic Toxicity of Pet Food Contaminated With Melamine and Cyanuric Acid in Rats.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
In conclusion, the combination ratio of cyanuric acid to melamine and the acidic urine content were two factors that, upon repeated exposure, determined the severity of the nephrotoxicity. PMID: 19801503 [PubMed - as supplied by publisher] (Source: Toxicologic Pathology)
Source: Toxicologic Pathology - October 1, 2009 Category: Pathology Authors: Chen KC, Liao CW, Cheng FP, Chou CC, Chang SC, Wu JH, Zen JM, Chen YT, Liao JW Tags: Toxicol Pathol Source Type: journals

Characterisation of Fibrodysplasia in the dog Following Inhibition of Metalloproteinases.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
We describe here histopathological findings during dog studies with a fairly selective MMPi AZM551248, that are consistent with these human clinical changes. They were characterized by a dose- and time-dependent formative connective tissue alteration we have termed "fibrodysplasia." The most sensitive site was the subcuticular connective tissue, although musculoskeletal tissues were also extensively involved. In the subcutis, changes occurred initially around pre-existing blood vessels, but then more diffusely. There was proliferation of cells showing myofibroblast differentiation identified by elevated levels of alpha-smo...
Source: Toxicologic Pathology - October 1, 2009 Category: Pathology Authors: Westwood R, Scott RC, Somers RL, Coulson M, Maciewicz RA Tags: Toxicol Pathol Source Type: journals

The role of the toxicologic pathologist in risk management.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
PMID: 19773592 [PubMed - in process] (Source: Toxicologic Pathology)
Source: Toxicologic Pathology - September 24, 2009 Category: Pathology Authors: Ochoa R, Rousseaux C Tags: Toxicol Pathol Source Type: journals

Systemic inflammatory response syndrome in nonhuman primates culminating in multiple organ failure, acute lung injury, and disseminated intravascular coagulation.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
We present five cases in the pig-tailed macaque and olive baboon where SIRS resulted in MOF, ARDS, DIC, and the Waterhouse-Friderichsen syndrome; each with gross and histological elements manifested as edema, deposition of fibrin, hemorrhage, and thrombosis. In the described cases, SIRS was the end-common pathway for multiple risk factors that parallel those documented in humans: major surgery, obstetric complications, and infection. The diagnosis of SIRS should be considered when evaluating nonhuman primate (NHP) cases of MOF manifesting with histological evidence of vascular leakage. Experimental manipulation of NHP mode...
Source: Toxicologic Pathology - September 24, 2009 Category: Pathology Authors: Hukkanen RR, Liggitt HD, Murnane RD, Frevert CW Tags: Toxicol Pathol Source Type: journals

Intralobar nephroblastematosis in a nine-week-old Wistar rat.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Intralobar nephroblastematosis (ILNB) is a precursor lesion to the development of nephroblastoma (NB) in rats. Unilateral ILNB was observed in the kidney of a nine-week-old female Wistar rat (Crl:WI) from a short-term toxicity study. Clinical pathology and urinalysis did not reveal altered renal function. This microscopic, unencapsulated lesion consisted of basophilic sheets of blastemal cells that did not include a prominent mesenchymal component. These cells expanded in the interstitium, which trapped and compressed few normal renal tubules. The blastemal cells moderately differentiated to form rosettes, primitive tu...
Source: Toxicologic Pathology - September 24, 2009 Category: Pathology Authors: Kalaiselvan P, Mathur KY, Pande VV, Madheswaran R, Bhelonde JJ, Shelar PD, Udupa V, Shingatgeri VM Tags: Toxicol Pathol Source Type: journals

Subcutaneous and Intraperitoneal Lipogranulomas Following Subcutaneous Injection of Olive Oil in Sprague-Dawley Rats.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Olive oil is commonly employed as a solubilizing agent for lipophilic materials in preclinical studies in rodents. Here we report that following subcutaneous (SC) injection of olive oil to Sprague-Dawley (SD) rats, local SC lipogranulomas formed, which were associated with an unusual location of the same changes in the peritoneum. Macroscopically, multifocal white spots were found over the liver and mesentery. Histologically, lipid granulomas were seen in the SC injection site, as well as on the capsular or serosal surface of the abdominal organs. No abnormal clinical signs were noted except for swelling at the injecti...
Source: Toxicologic Pathology - September 20, 2009 Category: Pathology Authors: Ramot Y, Eliahu SB, Kagan L, Ezov N, Nyska A Tags: Toxicol Pathol Source Type: journals

The Pivotal Role of Electron Microscopic Evaluation in Investigation of the Cardiotoxicity of bis(2-chloroethoxy)methane in Rats and Mice.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Electron microscopy and light microscopy have been used to evaluate the cardiotoxicity of bis(2-chloroethoxy)methane (CEM) in F344/N rats and B6C3F1 mice. Rats received vehicle control or CEM at 50 mg/kg/day, and mice, vehicle control or CEM at doses up to 100 mg/kg/day, by oral gavage for up to sixteen days. Cardiotoxicity in rats at 50 mg/kg consisted of myocardial degeneration, including myocardial inflammation, myofiber vacuolation, and/or myofiber necrosis. There was no light microscopic evidence for cardiotoxicity in mice even at doses twice that of rats, but cardiotoxic damage was seen after electron microscopic...
Source: Toxicologic Pathology - September 20, 2009 Category: Pathology Authors: Nyska A, Cunningham M, Snell M, Malarkey D, Sutton D, Dunnick J Tags: Toxicol Pathol Source Type: journals

Spontaneous Cardiomyopathy in Cynomolgus Monkeys (Macaca Fascicularis).Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
This report documents another spontaneous heart lesion in clinically healthy monkeys for consideration during interpretation of toxicology studies. PMID: 19706931 [PubMed - as supplied by publisher] (Source: Toxicologic Pathology)
Source: Toxicologic Pathology - August 24, 2009 Category: Pathology Authors: Zabka TS, Irwin M, Albassam MA Tags: Toxicol Pathol Source Type: journals

Regulatory Forum for Toxicologic Pathology: A 2 Year Update.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
PMID: 19706932 [PubMed - as supplied by publisher] (Source: Toxicologic Pathology)
Source: Toxicologic Pathology - August 24, 2009 Category: Pathology Authors: Schafer K, Francke-Carroll S, Hutto D, Neef N, Silverman L, Vahle J, Whitney K Tags: Toxicol Pathol Source Type: journals

Longitudinal Studies of Cardiac Troponin-I Concentrations in Serum from Male Sprague Dawley Rats: Baseline Reference Ranges and Effects of Handling and Placebo Dosing on Biological Variability.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
In this study, we used an ultrasensitive cTnI immunoassay to quantify hourly concentrations of cTnI in live rats handled under standard laboratory conditions using 15 microL of serum per determination. The baseline reference range (mean 4.94 pg/mL, range 1-15 pg/mL, 99% confidence interval [CI]) of cTnI concentration in rats was consistent with previously reported reference ranges for cTnI in humans (1-12 pg/mL) and with preliminary studies in dogs (1-4 pg/mL) and monkeys (4-5 pg/mL) using the same cTnI assay method. In addition, cTnI concentrations in individual rat serum samples show minimal biological variability over a...
Source: Toxicologic Pathology - August 20, 2009 Category: Pathology Authors: Schultze AE, Carpenter KH, Wians FH, Agee SJ, Minyard J, Lu QA, Todd J, Konrad RJ Tags: Toxicol Pathol Source Type: journals

Activation of Calcitonin Gene-Related Peptide Receptor during Ozone Inhalation Contributes to Airway Epithelial Injury and Repair.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The authors investigated the importance of the neuropeptide, calcitonin gene-related peptide (CGRP), in epithelial injury, repair, and neutrophil emigration after ozone exposure. Wistar rats were administered either a CGRP-receptor antagonist (CGRP8-37) or saline and exposed to 8 hours of 1-ppm ozone or filtered air with an 8-hour postexposure period. Immediately after exposure, ethidium homodimer was instilled into lungs as a marker of necrotic airway epithelial cells. After fixation, airway dissected lung lobes were stained for 5'-bromo-2'-deoxyuridine, a marker of epithelial proliferation. Positive epithelial cells ...
Source: Toxicologic Pathology - August 20, 2009 Category: Pathology Authors: Oslund KL, Hyde DM, Putney LF, Alfaro MF, Walby WF, Tyler NK, Schelegle ES Tags: Toxicol Pathol Source Type: journals

A Data-Based Assessment of Alternative Strategies for Identification of Potential Human Cancer Hazards.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The two-year cancer bioassay in rodents remains the primary testing strategy for in-life screening of compounds that might pose a potential cancer hazard. Yet experimental evidence shows that cancer is often secondary to a biological precursor effect, the mode of action is sometimes not relevant to humans, and key events leading to cancer in rodents from nongenotoxic agents usually occur well before tumorigenesis and at the same or lower doses than those producing tumors. The International Life Sciences Institute (ILSI) Health and Environmental Sciences Institute (HESI) hypothesized that the signals of importance for h...
Source: Toxicologic Pathology - August 20, 2009 Category: Pathology Authors: Boobis AR, Cohen SM, Doerrer NG, Galloway SM, Haley PJ, Hard GC, Hess FG, Macdonald JS, Thibault S, Wolf DC, Wright J Tags: Toxicol Pathol Source Type: journals

Neoplastic and Non-neoplastic Changes in F-344 Rats Treated with Naveglitazar, a g-Dominant PPAR a/g Agonist.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The carcinogenic potential of naveglitazar, a gamma-dominant peroxisome proliferator-activated receptor (PPAR) alpha/gamma dual agonist, was evaluated in a two-year study in F344 rats (0, 0.3, 1.0, or 3.0 mg/kg, males; 0, 0.1, 0.3, or 1.0 mg/kg, females). Increased mortality in male rats of the high-dose group was related to cardiac-associated lesions, neoplasms, and undetermined causes. Degeneration and hypertrophy of the myocardium occurred with dose-responsive increased incidence and severity. Neoplasms with increased incidence included sarcomas in male rats and urinary bladder neoplasms in female rats. Most sarcoma...
Source: Toxicologic Pathology - August 20, 2009 Category: Pathology Authors: Long GG, Reynolds VL, Dochterman LW, Ryan TE Tags: Toxicol Pathol Source Type: journals

Effects of Antifungal Agent, Itraconazole on Proliferative Changes of Forestomach Mucosa in Alloxan-Induced Diabetic Rats.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Alloxan-induced diabetic rats frequently exhibit proliferative lesions of squamous hyperplasia accompanied by chronic inflammation and Candida albicans infection in the forestomach, and some lesions progress to squamous cell carcinoma (SCC). Candida infection causes not only hyperplastic changes with inflammation but might also lead to SCC in human oral mucosa. Thus, the present study was conducted to examine the effects of the antifungal agent itraconazole (ITCZ) on proliferative and inflammatory changes of the forestomach in alloxan-induced diabetic WBN/Kob rats. Diabetes was induced by alloxan at fifteen weeks of ag...
Source: Toxicologic Pathology - August 20, 2009 Category: Pathology Authors: Sano T, Ozaki K, Kodama Y, Matsuura T, Narama I Tags: Toxicol Pathol Source Type: journals

Kainic Acid-induced F-344 Rat model of Mesial Temporal Lobe Epilepsy: Gene Expression and Canonical Pathways.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Mesial temporal lobe epilepsy (MTLE) is a severe neurological condition of unknown pathogenesis for which several animal models have been developed. To obtain a better understanding of the underlying molecular mechanisms and identify potential biomarkers of lesion progression, we used a rat kainic acid (KA) treatment model of MTLE coupled with global gene expression analysis to examine temporal (four hours, days 3, 14, or 28) gene regulation relative to hippocampal histopathological changes. The authors recommend reviewing the companion histopathology paper (Sharma et al. 2008) to get a better understanding of the work...
Source: Toxicologic Pathology - August 20, 2009 Category: Pathology Authors: Sharma AK, Searfoss GH, Reams RY, Jordan WH, Snyder PW, Chiang AY, Jolly RA, Ryan TP Tags: Toxicol Pathol Source Type: journals

Emanuel Edward Klein - The Father of British Microbiology and the Case of the Animal Vivisection Controversy of 1875.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The new Appendix A of the European Convention for the Protection of Vertebrate Animals Used for Experimental and Other Scientific Purposes, which gives guidelines for accommodation and care of animals and was approved on June 15, 2006, was the main reason the authors decided to investigate the origins of the regulations of animal experiments. Although one might assume that the regulation had its origin in the United Nations conventions, the truth is that its origins are a hundred years old. The authors present a case of the nineteenth-century vivisection controversy brought about by the publication of the Handbook for ...
Source: Toxicologic Pathology - August 17, 2009 Category: Pathology Authors: Atalic B, Fatovic-Ferencic S Tags: Toxicol Pathol Source Type: journals

Administration of Miltefosine and Meglumine Antimoniate in Healthy Dogs: Clinicopathological Evaluation of the Impact on the Kidneys.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
In conclusion, although no clinical signs of renal disease were evident, the use of meglumine antimoniate in the pharmacological treatment approach of CanL-affected dogs should be carefully considered. PMID: 19690151 [PubMed - as supplied by publisher] (Source: Toxicologic Pathology)
Source: Toxicologic Pathology - August 17, 2009 Category: Pathology Authors: Bianciardi P, Brovida C, Valente M, Aresu L, Cavicchioli L, Vischer C, Giroud L, Castagnaro M Tags: Toxicol Pathol Source Type: journals

Mechanistic Study on Hepatocarcinogenesis of Piperonyl Butoxide in Mice.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
To clarify the mechanism of piperonyl butoxide (PBO)-induced hepatocarcinogenesis in mice, male mice were subjected to a two-thirds partial hepatectomy, N-diethylnitrosamine (DEN) initiation, and a diet containing 0.6% PBO for eight weeks. The incidence of gamma-glutamyl transpeptidase (GGT)-positive foci and PCNA-positive cells was significantly increased in the DEN + PBO group compared with the DEN-alone group. Real-time reverse transcription-polymerase chain reaction (RT-PCR) analysis showed up-regulation of genes related to metabolism, such as cytochrome P450 1A1 and 2B10, and metabolic stress, such as Por, Nqo1, N...
Source: Toxicologic Pathology - August 17, 2009 Category: Pathology Authors: Kawai M, Saegusa Y, Jin M, Dewa Y, Nishimura J, Harada T, Shibutani M, Mitsumori K Tags: Toxicol Pathol Source Type: journals

Carcinogenic Effects of MGP-7 and B[a]P on the Hamster Cheek Pouch.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
This study was performed to examine the carcinogenic effects of benzo[a]pyrene (B[a]P) and manufactured gas plant (MGP) residues on the hamster cheek pouch (HCP). Syrian hamsters were treated topically with a suspension of 2%, 10%, or 20% B[a]P or 50% or 100% MGP-7 (a mixture of residues from 7 MGP sites) in mineral oil for eight (short-term study) and sixteen, twenty, twenty-eight, and thirty-two weeks (long-term study). The short-term study showed that B[a]P induced p53 protein accumulation, indicative of genotoxic damage, as well as increased cell proliferation, hyperplasia, and inflammation, which is usually associated...
Source: Toxicologic Pathology - August 12, 2009 Category: Pathology Authors: Brandon JL, Conti CJ, Goldstein LS, Digiovanni J, Gimenez-Conti IB Tags: Toxicol Pathol Source Type: journals

The re-emergence (or the decline) of toxicologic pathology.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
PMID: 19638439 [PubMed - in process] (Source: Toxicologic Pathology)
Source: Toxicologic Pathology - July 31, 2009 Category: Pathology Authors: Alden CL Tags: Toxicol Pathol Source Type: journals

Effects of a cyclooxygenase-2 preferential inhibitor in young healthy dogs exposed to air pollution: a pilot study.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Reynoso-Robles R, Villarreal-Calderon R, Patel SA, Kumarathasan P, Vincent R, Henríquez-Roldán C, Torres-Jardón R, Maronpot RR Residency in cities with high air pollution is associated with neuroinflammation and neurodegeneration in healthy children, young adults, and dogs. Nonsteroidal anti-inflammatory drugs may offer neuroprotection. The authors measured the plasma concentrations of 3-nitrotyrosine and the cerebro-spinal-fluid concentrations of prostaglandin E2 metabolite and the oligomeric form of amyloid derived diffusible ligand; measured the mRNA expression of cyclooxygenase-2, interleukin 1beta,...
Source: Toxicologic Pathology - July 31, 2009 Category: Pathology Authors: Calderón-Garcidueñas L, Mora-Tiscareño A, Gómez-Garza G, Carrasco-Portugal Mdel C, Pérez-Guillé B, Flores-Murrieta FJ, Pérez-Guillé G, Osnaya N, Juárez-Olguín H, Monroy ME, Monroy S, González-Maciel A Tags: Toxicol Pathol Source Type: journals

Potential for a global historical control database for proliferative rodent lesions.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
PMID: 19638441 [PubMed - in process] (Source: Toxicologic Pathology)
Source: Toxicologic Pathology - July 31, 2009 Category: Pathology Authors: Keenan C, Elmore S, Francke-Carroll S, Kerlin R, Peddada S, Pletcher J, Rinke M, Schmidt SP, Taylor I, Wolf DC Tags: Toxicol Pathol Source Type: journals

The international nomenclature project: an update.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
PMID: 19638442 [PubMed - in process] (Source: Toxicologic Pathology)
Source: Toxicologic Pathology - July 31, 2009 Category: Pathology Authors: Vahle J, Bradley A, Harada T, Herbert R, Kaufmann W, Kellner R, Mann P, Pyrah I, Rittinghausen S, Tanaka T Tags: Toxicol Pathol Source Type: journals

Histopathological Features of Capillaria hepatica Infection in Laboratory Rabbits.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Capillaria hepatica is a nematode parasite of wild rodents and other mammals. Adult worms inhabit the liver. Recently, during the necropsy examination of a group of 160 rabbits from a commercial supplier, firm pale or cystic areas (1-5 mm) were noted on the liver in thirteen animals. On further investigation, these animals were found to be infected with C. hepatica. The histopathological features of the infection in the rabbit are described for the first time and diagnostic features recorded. Lesions were identified predominantly in portal tracts consisting of dilated bile ducts with luminal debris, peribiliary inflamm...
Source: Toxicologic Pathology - June 30, 2009 Category: Pathology Authors: Mowat V, Turton J, Stewart J, Lui KC, Pilling AM Tags: Toxicol Pathol Source Type: journals

Histology atlas of the developing mouse heart with emphasis on E11.5 to E18.5.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
In humans, congenital heart diseases are common. Since the rapid progression of transgenic technologies, the mouse has become the major animal model of defective cardiovascular development. Moreover, genetically modified mice frequently die in utero, commonly due to abnormal cardiovascular development. A variety of publications address specific developmental stages or structures of the mouse heart, but a single reference reviewing and describing the anatomy and histology of cardiac developmental events, stage by stage, has not been available. The aim of this color atlas, which demonstrates embryonic/fetal heart develop...
Source: Toxicologic Pathology - June 27, 2009 Category: Pathology Authors: Savolainen SM, Foley JF, Elmore SA Tags: Toxicol Pathol Source Type: journals

Regulatory forum.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
PMID: 19380838 [PubMed - indexed for MEDLINE] (Source: Toxicologic Pathology)
Source: Toxicologic Pathology - June 27, 2009 Category: Pathology Authors: Foster JR Tags: Toxicol Pathol Source Type: journals

Discovery of metabolomics biomarkers for early detection of nephrotoxicity.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Drug-induced nephrotoxicity is a major concern, since many pharmacological compounds are filtered through the kidneys for excretion into urine. To discover biochemical biomarkers useful for early identification of nephrotoxicity, metabolomic experiments were performed on Sprague-Dawley Crl:CD (SD) rats treated with the nephrotoxins gentamicin, cisplatin, or tobramycin. Using a combination of gas chromatography/mass spectrometry (GC/MS) and liquid chromatography/mass spectrometry (LC/MS), a global, nontargeted metabolomics analysis was performed on urine and kidney samples collected after one, five, and twenty-eight dos...
Source: Toxicologic Pathology - June 27, 2009 Category: Pathology Authors: Boudonck KJ, Mitchell MW, Német L, Keresztes L, Nyska A, Shinar D, Rosenstock M Tags: Toxicol Pathol Source Type: journals

Strain-related differences in urine composition of male rats of potential relevance to urolithiasis.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
In carcinogenicity studies with PPAR gamma and alpha/gamma agonists, urinary bladder tumors have been reported in Harlan Sprague-Dawley (HSD) and Charles River Sprague-Dawley (SD) but not Wistar (WI) rats, with urolithiasis purported to be the inciting event. In two 3-month studies, the authors investigated strain-related differences in urine composition by sampling urine multiple times daily. Urine pH, electrolytes, creatinine, protein, citrate and oxalate levels, and serum citrate were assessed; urine sediment was analyzed by scanning electron microscopy and energy dispersive x-ray spectroscopy. HSD rats had signific...
Source: Toxicologic Pathology - June 27, 2009 Category: Pathology Authors: Tannehill-Gregg SH, Dominick MA, Reisinger AJ, Moehlenkamp JD, Waites CR, Stock DA, Sanderson TP, Cohen SM, Arnold LL, Schilling BE Tags: Toxicol Pathol Source Type: journals

Eosinophilic inclusions in rat Clara cells and the effect of an inhaled corticosteroid.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Large eosinophilic cytoplasmic inclusions (ECIs) are occasionally seen in untreated rat Clara cells. Following inhalation exposure to a corticosteroid, the number of ECIs was increased. This is the first histopathological description of rat ECIs and attempted characterization by immunohistochemistry, in situ hybridization, and electron microscopy. ECIs were strongly positive for surfactant protein D (SP-D) and weakly positive for Clara cell specific protein (CCSP). Clara cell cytoplasm was positive for CCSP mRNA regardless of ECIs, but not within ECIs. Corticosteroid treatment and ECI presence did not affect the immuno...
Source: Toxicologic Pathology - June 27, 2009 Category: Pathology Authors: Kambara T, McKevitt TP, Francis I, Woodfine JA, McCawley SJ, Jones SA, Pilling AM, Lewis DJ, Williams TC Tags: Toxicol Pathol Source Type: journals

Effects of chronic exposure to crack cocaine on the respiratory tract of mice.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Smoked cocaine (crack cocaine) causes several forms of injury to the respiratory tract, including asthma exacerbations, lung edema and hemorrhage, and nasal mucosal alterations. Few studies, however, have assessed respiratory tract pathology in habitual users of crack cocaine. Here, we describe the histological alterations in the respiratory tract of mice caused by chronic inhalation of crack cocaine. Twenty 2-month-old BALB/c mice were exposed to the smoke of 5 g crack cocaine in an inhalation chamber once a day for two months and compared to controls (n = 10). We then morphometrically analyzed nose and bronchiolar ep...
Source: Toxicologic Pathology - June 27, 2009 Category: Pathology Authors: Herculiani PP, Pires-Neto RC, Bueno HM, Zorzetto JC, Silva LC, Santos AB, Garcia RC, Yonamine M, Detregiachi CR, Saldiva PH, Mauad T Tags: Toxicol Pathol Source Type: journals

Spontaneous ganglioneuroma possibly originating from the trigeminal ganglion in a B6C3F1 mouse.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
This report provides additional histopathological evidence of peripheral nerve neoplasms in mice. PMID: 19380843 [PubMed - indexed for MEDLINE] (Source: Toxicologic Pathology)
Source: Toxicologic Pathology - June 27, 2009 Category: Pathology Authors: Yasui Y, Ohta Y, Ueda Y, Hasegawa K, Kihara T, Hosoi M, Miyajima R, Shiga A, Imai K, Toyoda K Tags: Toxicol Pathol Source Type: journals