Abstract：
:One application of genomics in drug safety assessment is the identification of biomarkers to predict compound toxicity before it is detected using traditional approaches, such as histopathology. However, many genomic approaches have failed to demonstrate superiority to traditional methods, have not been appropriately validated on external samples, or have been derived using small data sets, thus raising concerns of their general applicability. Using kidney gene expression profiles from male SD rats treated with 64 nephrotoxic or non-nephrotoxic compound treatments, a gene signature consisting of only 35 genes was derived to predict the future development of renal tubular degeneration weeks before it appears histologically following short-term test compound administration. By comparison, histopathology or clinical chemistry fails to predict the future development of tubular degeneration, thus demonstrating the enhanced sensitivity of gene expression relative to traditional approaches. In addition, the performance of the signature was validated on 21 independent compound treatments structurally distinct from the training set. The signature correctly predicted the ability of test compounds to induce tubular degeneration 76% of the time, far better than traditional approaches. This study demonstrates that genomic data can be more sensitive than traditional methods for the early prediction of compound-induced pathology in the kidney.
journal_name
Toxicol Patholjournal_title
Toxicologic pathologyauthors
Fielden MR,Eynon BP,Natsoulis G,Jarnagin K,Banas D,Kolaja KLdoi
10.1080/01926230500321213subject
Has Abstractpub_date
2005-01-01 00:00:00pages
675-83issue
6eissn
0192-6233issn
1533-1601pii
T06867K6170G4R68journal_volume
33pub_type
杂志文章abstract：:A factor limiting widespread use of the transgenic rasH2 mouse model for carcinogenicity testing of pharmaceuticals is the paucity of published data on actual drug candidates in rasH2 mice. This report addresses this gap by highlighting rasH2 mouse study data for 10 pharmaceutical candidates. These results were compar...
journal_title：Toxicologic pathology
pub_type： 杂志文章
doi：10.1177/0192623313477257
更新日期：2013-01-01 00:00:00
abstract：:Phosphatidylinositol 3-kinases (PI3Ks) regulate intracellular signaling events for multiple cell surface receptors. Phosphatidylinositol 3-kinase δ, 1 of 4 class I PI3K isoforms, is primarily found in leukocytes and regulates immune cell functions. Here, we report changes in the immune and digestive systems that were ...
journal_title：Toxicologic pathology
pub_type： 杂志文章
doi：10.1177/0192623320966238
更新日期：2020-12-01 00:00:00
abstract：:Sensitive kidney safety assessment is important for successful drug development in both preclinical and clinical stages. The Food and Drug Administration recently qualified a composite measure of 6 urine creatinine-normalized biomarkers, such as clusterin, cystatin C, kidney injury molecule 1 (KIM-1), N-acetyl-β-d-glu...
journal_title：Toxicologic pathology
pub_type： 杂志文章
doi：10.1177/0192623320964391
更新日期：2020-12-01 00:00:00
abstract：:To characterize genetic alterations occurring in renal tumorigenesis, EHEN-induced renal cell tumors were examined using restriction landmark genomic scanning (RLGS) analysis, an electrophoretic separation technique that detects gene amplifications and deletions. Comparison of DNAs from tumor against those from corres...
journal_title：Toxicologic pathology
pub_type： 杂志文章
doi：10.1080/019262301317052503
更新日期：2001-03-01 00:00:00
abstract：:Age-related changes in gross and microscopic structure of the nasal cavity may alter local tissue susceptibility as well as the dose of inhaled toxicant delivered to susceptible sites. This article describes a novel method for the use of magnetic resonance imaging, 3-dimensional airway modeling, and morphometric techn...
journal_title：Toxicologic pathology
pub_type： 杂志文章,多中心研究
doi：10.1080/01926230601072343
更新日期：2007-01-01 00:00:00
abstract：:Hepatic microsomal enzymes play an important role in thyroid hormone homeostasis. Glucuronidation of thyroxine is the rate limiting step in the biliary excretion of thyroxine in the rat; the monodeiodinases are important in the conversion of T4 to T3 and reverse T3 and subsequent deiodinations. Phenobarbital is known ...
journal_title：Toxicologic pathology
pub_type： 杂志文章,评审
doi：10.1177/019262338901700206
更新日期：1989-01-01 00:00:00
abstract：:Vaginal exfoliative cytology is commonly used in biomedical and toxicological research to classify the stages of the rodent estrous cycle. However, mouse vaginal exfoliative cytology is commonly used as a stand-alone tool and has not been evaluated in reference to vaginal histology and serum sex hormone levels. In thi...
journal_title：Toxicologic pathology
pub_type： 杂志文章
doi：10.1177/0192623314526321
更新日期：2014-12-01 00:00:00
abstract：:Necropsies conducted to support medical device development may be conducted in facilities that do not have the infrastructure in place to support Good Laboratory Practice for Nonclinical Laboratory Studies (GLP) studies and for a variety of reasons they may be conducted without a pathologist present at necropsy. Howev...
journal_title：Toxicologic pathology
pub_type： 杂志文章
doi：10.1177/0192623315617035
更新日期：2016-01-01 00:00:00
abstract：:The usefulness of isolated adult cardiac myocytes, both in suspension and in culture, as a model system for measuring cardiotoxicity is evaluated. It has been suggested that isolated adult myocytes should preferably be cultured for such experimentation, as this restores the cells to a physiological preference for fatt...
journal_title：Toxicologic pathology
pub_type： 杂志文章
doi：
更新日期：1990-01-01 00:00:00
abstract：:The common marmoset, Callithrix jacchus, is the smallest nonhuman primate commonly used in biomedical research. Marmoset characteristics and propensities have enabled them to be used in a wide range of research as a model of human disease, physiology, drug metabolism, general toxicology, and reproductive biology. This...
journal_title：Toxicologic pathology
pub_type： 杂志文章,评审
doi：10.1080/01926230390175002
更新日期：2003-01-01 00:00:00
abstract：:Studies of xenobiotic biotransformation by in vitro techniques are destined to play an increasingly important role in assessing the safety and efficacy of drugs and other new chemical entities. The first part of this article summarizes some of the in vitro techniques that have been developed to evaluate xenobiotics as...
journal_title：Toxicologic pathology
pub_type： 杂志文章,评审
doi：
更新日期：1996-01-01 00:00:00
abstract：:Regulatory guidelines for nonclinical neurotoxicity testing require spinal cord evaluation but do not specify a trimming scheme. The Society of Toxicologic Pathology (STP) "best practices" for nervous system sampling during nonclinical general toxicity studies recommend that spinal cord be assessed in both longitudina...
journal_title：Toxicologic pathology
pub_type： 杂志文章
doi：10.1177/0192623317720120
更新日期：2017-07-01 00:00:00
abstract：:Artemin (ART) signals through the GFR alpha-3/RET receptor complex to support sympathetic neuron development. Here we show that ART also influences autonomic elements in adrenal medulla and enteric and pelvic ganglia. Transgenic mice over-expressing Art throughout development exhibited systemic autonomic neural lesion...
journal_title：Toxicologic pathology
pub_type： 杂志文章
doi：10.1080/01926230490431475
更新日期：2004-05-01 00:00:00
abstract：:Congenital anomalies of the alimentary tract are rare lesions in laboratory animals. We describe a congenital cyst attached to the greater curvature of the forestomach in a B6C3F1 mouse. The inner surface of the cyst was mostly covered with cuboidal or pseudostratified ciliated epithelium and was focally covered with ...
journal_title：Toxicologic pathology
pub_type： 杂志文章
doi：10.1177/019262339902700514
更新日期：1999-09-01 00:00:00
abstract：:Qualitative histopathology has been the gold standard for evaluation of morphological tissue changes in all organ systems, including the peripheral nervous system. However, the human eye is not sensitive enough to detect small changes in quantity or size. Peripheral nervous system toxicity can manifest as subtle chang...
journal_title：Toxicologic pathology
pub_type： 杂志文章
doi：10.1177/0192623319854746
更新日期：2020-01-01 00:00:00
abstract：:We believe the development and validation of in vitro alternatives to eliminate the need to use animals in ocular irritation testing must be based on a thorough understanding of the mechanisms of ocular irritation. We have recently undertaken the task of developing such an understanding for a panel of surfactants. The...
journal_title：Toxicologic pathology
pub_type： 杂志文章
doi：10.1177/019262339802600206
更新日期：1998-03-01 00:00:00
abstract：:Congenital intrahepatic arteriovenous fistulae, a rare hepatic vascular anomaly, in an 8-mo-old female beagle dog was investigated. The animal showed anorexia, repeated vomiting, hemorrhagic diarrhea, and jaundice for approximately 2 wk. There was mild to severe increase of serum alkaline phosphatase, glutamic-oxalace...
journal_title：Toxicologic pathology
pub_type： 杂志文章
doi：10.1177/019262339702500511
更新日期：1997-09-01 00:00:00
abstract：:The first part of this paper focuses on the secondary immunodeficiencies caused by immunosuppressive drugs and environmental chemicals. The mechanism of action and the therapeutic effects of azathioprine, glucocorticosteroids, cyclophosphamide, cyclosporin A, and anticancer drugs will be discussed. The immunotoxic act...
journal_title：Toxicologic pathology
pub_type： 杂志文章,评审
doi：10.1177/019262338701500310
更新日期：1987-01-01 00:00:00
abstract：:Hyaline droplet formation in the proximal tubular cells of the kidney commonly occurs under different pathological conditions in experimental animals. In rats, intracytoplasmic hyaline droplet formation is predominantly associated with accumulation of the male rat-specific alpha(2u)-globulin, whereas under other (path...
journal_title：Toxicologic pathology
pub_type： 杂志文章
doi：10.1080/01926230390213775
更新日期：2003-07-01 00:00:00
abstract：:Two-year toxicity studies were conducted on the widely used herbal products, goldenseal and milk thistle, in male and female F344/N rats and B6C3F1 mice. With goldenseal root powder, the primary finding was an increase in liver tumors in rats and mice, and with milk thistle extract, a decrease in spontaneous backgroun...
journal_title：Toxicologic pathology
pub_type： 杂志文章
doi：10.1177/0192623310394211
更新日期：2011-02-01 00:00:00
abstract：:The nonnucleoside inhibitor (NNI) of HIV-1 reverse transcriptase, PHI-346 (N-[2-(1-cyclohexenyl)ethyl]-N'-[2-(5-bromopyridyl)]-thiourea), is a dual-function spermicidal agent with potent anti-HIV activity against drug-sensitive as well as drug-resistant HIV-1 strains with genotypic and phenotypic NNI resistance. PHI-3...
journal_title：Toxicologic pathology
pub_type： 杂志文章
doi：10.1080/01926230290168551
更新日期：2002-11-01 00:00:00
abstract：:Recommendations (best practices) are provided by the Society of Toxicologic Pathology's Adversity Working Group for making consistent interpretations of test article-related effects as "adverse" and assigning a "no observed adverse effect level" (NOAEL) in nonclinical toxicity studies. Adverse is a term indicating "ha...
journal_title：Toxicologic pathology
pub_type： 杂志文章
doi：10.1177/0192623315623265
更新日期：2016-02-01 00:00:00
abstract：:Recently, considerable attention has been focused on certain environmental contaminants--"endocrine disruptors"--of industrial origin that may mimic the action of sex hormones. Natural compounds and their effects on other types of hormonal activity (eg, on adrenal or thyroid function) have for some reason not provoked...
journal_title：Toxicologic pathology
pub_type： 杂志文章,评审
doi：10.1177/019262330002800311
更新日期：2000-05-01 00:00:00
abstract：:Repeated intraperitoneal injections of crocidolite asbestos fibers induced diffuse malignant mesotheliomas in mice. A series of mesothelial cell lines was isolated from mice at different stages in the development of these tumors. The cell lines isolated from mice with mesotheliomas recapitulated their growth pattern i...
journal_title：Toxicologic pathology
pub_type： 杂志文章
doi：10.1177/019262339702500605
更新日期：1997-11-01 00:00:00
abstract：:Colorectal cancer, responsible for 50,000 deaths per year, is a contributing factor for considerable mortalities in the United States. Consumption of well-done red meat and saturated fats rich in polycyclic aromatic hydrocarbons may be one of the causative factors for sporadic colon cancer. The objective of this study...
journal_title：Toxicologic pathology
pub_type： 杂志文章
doi：10.1177/0192623309351722
更新日期：2009-12-01 00:00:00
abstract：:Duplications of the gastrointestinal tract are exceedingly rare in laboratory animals. We report a case of a communicating intestinal duplication in a 17-wk-old Sprague-Dawley (SD) rat. The duplication was present in the mesenteric border of the ileum, and both proximal and distal ends were communicated with the lumen...
journal_title：Toxicologic pathology
pub_type： 杂志文章
doi：10.1177/019262339802600216
更新日期：1998-03-01 00:00:00
abstract：:The 2015 Annual National Toxicology Program Satellite Symposium, entitled "Pathology Potpourri" was held in Minneapolis, Minnesota, at the American College of Veterinary Pathologists/American Society for Veterinary Clinical Pathology/Society of Toxicologic Pathology combined meeting. The goal of this symposium is to p...
journal_title：Toxicologic pathology
pub_type：
doi：10.1177/0192623316631844
更新日期：2016-06-01 00:00:00
abstract：:In tissue slice models, interactions between the heterogeneous cell types comprising the lung parenchyma are maintained thus providing a controlled system for the study of pulmonary toxicology in vitro. However, validation of the model in vitro system must be affirmed. Previous reports, in in vivo systems, have demons...
journal_title：Toxicologic pathology
pub_type： 杂志文章
doi：10.1080/01926230390183689
更新日期：2003-03-01 00:00:00
abstract：:Pentostatin, an adenosine deaminase inhibitor, has been approved for the treatment of refractory hairy cell leukemia. In a preclinical toxicity study, Wistar rats were administered 0, 1, 10, 25, and 50 mg/kg (0, 6, 60, 150, and 300 mg/m2, respectively) pentostatin intravenously once a week for 26 wk (1.5-75-fold above...
journal_title：Toxicologic pathology
pub_type： 杂志文章
doi：10.1177/019262339402200506
更新日期：1994-09-01 00:00:00
abstract：:This report describes the findings of preclinical testing of SCH 351591, a selective phosphodiesterase 4 inhibitor, in CD-1 mice over a wide range of doses, in which the heart and reproductive organs of both sexes demonstrated toxic effects. Repeat-dose toxicity studies assessed 5, 15, 50, 100, 200, 400, and 800 mg/kg...
journal_title：Toxicologic pathology
pub_type： 杂志文章
doi：10.1177/0192623310370463
更新日期：2010-06-01 00:00:00
