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-glucosaminidase, neutrophil gelatinase-associated lipocalin (NGAL), and osteopontin, for monitoring kidney toxicity in early clinical trials. The qualification was based on small molecule drugs in humans, and the full panel has not been assessed in other species or for other drug modalities. This study evaluated the effects on these biomarkers for a constrained ethyl antisense oligonucleotide (tool ASO) with demonstrated kidney toxicity in mice compared to a control ASO of the same chemistry. Dosing 50 mg/kg of the tool ASO resulted in mild proximal tubular pathology and elevations in KIM-1, clusterin, NGAL, and cystatin C. A lower dose resulted in milder histopathology and lower biomarker increases. Unexpectedly, the control ASO induced mild elevations in KIM-1, NGAL, and cystatin C, despite the lack of pathology. Both KIM-1 and clusterin were most closely associated with kidney pathology and increased with the severity of injury. Altogether, our data suggest that a biomarker panel is a sensitive tool for the detection of preclinical ASO-induced kidney pathology.
journal_name
Toxicol Patholjournal_title
Toxicologic pathologyauthors
Sandelius Å,Basak J,Hölttä M,Sultana S,Hyberg G,Wilson A,Andersson P,Söderberg Mdoi
10.1177/0192623320964391subject
Has Abstractpub_date
2020-12-01 00:00:00pages
981-993issue
8eissn
0192-6233issn
1533-1601journal_volume
48pub_type
杂志文章abstract：:Laser scanning cytometry (LSC) is a powerful tool for qualitative and quantitative analysis of tissue sections in preclinical drug development. LSC combines the strengths of flow cytometry with tissue architecture retention. This technology has been used predominantly with immunofluorescent techniques on cell culture ...
journal_title：Toxicologic pathology
pub_type： 杂志文章,评审
doi：10.1177/0192623307312704
更新日期：2008-01-01 00:00:00
abstract：:The B6C3F1 strain of mice is prone to develop liver nodules as animals grow older. This spontaneous tumor development is enhanced by dietary lipotrope deficiency. The present studies were performed to evaluate the liver of the B6C3F1 mice in early periods of lipotrope deficiency and before the nodules appear. Mice wer...
journal_title：Toxicologic pathology
pub_type： 杂志文章
doi：10.1177/019262338501300103
更新日期：1985-01-01 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：:We examined the effects of the quinolone antibacterial agents pefloxacin (PFLX) and ofloxacin (OFLX) on the Achilles tendon of Sprague-Dawley rats. A single oral administration of PFLX 300 and 900 mg/kg or OFLX 900 mg/kg induced edema with mononuclear cell infiltration mainly in the inner sheath of the inner Achilles ...
journal_title：Toxicologic pathology
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doi：10.1177/019262339502300315
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abstract：:The chloracetanilide herbicide alachlor (2-chloro-2',6-diethyl-N-(methoxymethyl)-acetanilide) induces nasal neoplasms in rats following chronic dietary exposure. The present study sought to identify the cellular origin and mechanisms of tumor induction and progression. Male Long-Evans rats were fed alachlor (0 or 126 ...
journal_title：Toxicologic pathology
pub_type： 杂志文章
doi：10.1177/019262330002800602
更新日期：2000-11-01 00:00:00
abstract：:During preclinical investigations into the safety of drugs and chemicals, many are found to interfere with reproductive function in the female rat. This interference is commonly expressed as a change in normal morphology of the reproductive tract or a disturbance in the duration of particular phases of the estrous cyc...
journal_title：Toxicologic pathology
pub_type： 杂志文章,评审
doi：10.1177/0192623308315665
更新日期：2008-04-01 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：:We have previously indicated that the ideal animal tumor model should mimic the human disease. This means that the investigator should be able to ascertain the influence of host factors on the initiation of tumorigenesis, mimic the susceptibility of tumor response based on age and reproductive history, and determine t...
journal_title：Toxicologic pathology
pub_type： 杂志文章,评审
doi：10.1177/0192623314532036
更新日期：2015-02-01 00:00:00
abstract：:Direct tissue profiling and imaging mass spectrometry (MS) allow for detailed mapping of the complex protein pattern across a tissue sample. Utilization of these tools provides spatial information across a tissue section for target protein expression and can be used to correlate changes in expression levels with speci...
journal_title：Toxicologic pathology
pub_type： 杂志文章,评审
doi：10.1080/01926230590881862
更新日期：2005-01-01 00:00:00
abstract：:Swine, especially the miniature swine or minipigs, are increasingly being used in preclinical safety assessment of small molecules, biopharmaceutical agents, and medical devices as an alternate nonrodent species. Although swine have been used extensively in biomedical research, there is a paucity of information in the...
journal_title：Toxicologic pathology
pub_type： 杂志文章
doi：10.1177/0192623315611762
更新日期：2016-04-01 00:00:00
abstract：:Environmental pollutants, chemicals, and drugs have an impact on children's immune system development. Mexico City (MC) children exposed to significant concentrations of air pollutants exhibit chronic respiratory inflammation, systemic inflammation, neuroinflammation, and cognitive deficits. We tested the hypothesis t...
journal_title：Toxicologic pathology
pub_type： 杂志文章
doi：10.1177/0192623308329340
更新日期：2009-02-01 00:00:00
abstract：:The beagle is a monoestric, nonseasonal breeder with a long estrous cycle. Owing to lengthy stages in individual phases of the estrous cycle, limited group size, and typical group assignment focused on homogenized body weight, dogs in the same stage of the cycle can be inadvertently assigned to one treatment group in ...
journal_title：Toxicologic pathology
pub_type： 杂志文章
doi：10.1177/0192623308326150
更新日期：2008-12-01 00:00:00
abstract：:S-(1,2-dichlorovinyl)-L-cysteine (DCVC)-induced nephrotoxicity in vivo was investigated in New Zealand White rabbits. A primary emphasis in these studies was further characterization of DCVC-induced nephrotoxicity using a variety of serum and urinary analytes, including sodium dodecyl sulfate-polyacrylamide gel electr...
journal_title：Toxicologic pathology
pub_type： 杂志文章
doi：10.1177/019262339502300405
更新日期：1995-07-01 00:00:00
abstract：:In organs with diverse cell populations, it is not uncommon for one type of cell to respond while others are spared. Even in an organ with common cell types, such as hepatocytes within the liver, the population of cells may respond with different sensitivities for injury or for biochemical responses to toxicants. In t...
journal_title：Toxicologic pathology
pub_type： 杂志文章,评审
doi：10.1080/01926230252824789
更新日期：2002-01-01 00:00:00
abstract：:A compendium of carcinogenesis bioassay results organized by target organ is presented for 738 chemicals that are carcinogenic in chronic-exposure, long-term bioassays in at least 1 species. This compendium is based primarily on experiments in rats or mice; results in hamsters, monkeys, and dogs are also reported. The...
journal_title：Toxicologic pathology
pub_type： 杂志文章,评审
doi：10.1080/019262301753385979
更新日期：2001-11-01 00:00:00
abstract：:Sprague-Dawley CD rats received daily oral doses (45 mg/kg) of the cationic amphiphilic tricyclic antidepressant imipramine HCl (Tofranil) for up to two years. Representative specimens of liver, lung, spleen, mesenteric lymph node, retina and dorsal root ganglion were examined for myeloid bodies (MB). The extent that ...
journal_title：Toxicologic pathology
pub_type： 杂志文章
doi：10.1177/019262338301100102
更新日期：1983-01-01 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：: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：:Absorbable metallic implants have been under investigation for more than a century. Animal and human studies have shown that magnesium (Mg) alloys can be safely used in bioresorbable scaffolds. Several cardiovascular and orthopedic biodegradable metallic devices have recently been approved for use in humans. Bioresorb...
journal_title：Toxicologic pathology
pub_type： 杂志文章,评审
doi：10.1177/0192623318816936
更新日期：2019-04-01 00:00:00
abstract：:Liver resection is a suitable option for the treatment of certain hepatic conditions, particularly hepatocarcinomas, in patients with cirrhosis. However, this disease impairs liver regeneration, which increases the risk of liver failure and postoperative death. Supportive treatments for regeneration of the remaining l...
journal_title：Toxicologic pathology
pub_type： 杂志文章
doi：10.1177/0192623313486316
更新日期：2014-01-01 00:00:00
abstract：:The use of biodegradable materials is gaining popularity in medicine, especially in orthopedic applications. However, preclinical evaluation of biodegradable materials can be challenging, since they are located in close contact with host tissues and might be implanted for a long period of time. Evaluation of these com...
journal_title：Toxicologic pathology
pub_type： 杂志文章
doi：10.1177/0192623315600275
更新日期：2015-12-01 00:00:00
abstract：:The role of articular chondrocytes and matrix degrading enzymes such as collagenase and neutral protease in the pathogenesis of quinolone-induced cartilage degeneration was investigated in immature guinea pigs. Articular cartilage from nalidixic acid (NA) treated guinea pigs was examined for the presence of protease a...
journal_title：Toxicologic pathology
pub_type： 杂志文章
doi：10.1177/019262339001800209
更新日期：1990-01-01 00:00:00
abstract：:A comparative study of histochemical detection of eosinophils in fixed murine tissue is lacking. Five histochemical methods previously reported for eosinophil detection were quantitatively and qualitatively compared in an established murine RSV vaccine-enhanced inflammation model. Nonspecific neutrophil staining was e...
journal_title：Toxicologic pathology
pub_type： 杂志文章
doi：10.1177/0192623308329342
更新日期：2009-02-01 00:00:00
abstract：:To determine if additive or synergistic toxic effects would occur, adult male rats were exposed orally to lead carbonate (2,000 mg/kg) for 9 days before trichloroethylene (TCE), 2,000 mg/kg, was given concurrently for an additional 7 days. Comparisons were made with groups of vehicle-treated rats and rats given only l...
journal_title：Toxicologic pathology
pub_type： 杂志文章
doi：10.1080/01926230152499809
更新日期：2001-07-01 00:00:00
abstract：:The toxicity of hydroxyurea, a treatment for specific neoplasms, sickle-cell disease, polycythemia, and thrombocytosis that kills cells in mitosis, was assessed in repeat-dose, oral gavage studies in rats and dogs and a cardiovascular study in telemetered dogs. Hydroxyurea produced hematopoietic, lymphoid, cardiovascu...
journal_title：Toxicologic pathology
pub_type： 杂志文章
doi：10.1177/0192623314559103
更新日期：2015-06-01 00:00:00
abstract：:After 15 years of existence, the ACVP/STP Coalition for Veterinary Pathology Fellows will dissolve, primarily due to lack of renewed financial sponsorship. While in operation, the Coalition organized 32 new training position for veterinary pathologists, supported by $7.4 M from sponsors, including pharmaceutical and b...
journal_title：Toxicologic pathology
pub_type： 杂志文章
doi：10.1177/0192623320917970
更新日期：2020-06-01 00:00:00
abstract：:Animal models have provided an important tool to help make the decision to take potential therapies from preclinical studies to humans. In the past several years, the strong reliance of the pharmaceutical discovery and development process on the use of animal models has come under increasing scrutiny for ethical and s...
journal_title：Toxicologic pathology
pub_type： 杂志文章
doi：10.1177/0192623314555162
更新日期：2015-01-01 00:00:00
abstract：:In the present study, susceptibility of CB6F1 mice carrying the human prototype c-Ha-ras gene (rasH2 mice) and p53 gene knockout mice (p53 (+/-) mice) to urethane-induced lung carcinogenesis was compared under the same experimental conditions. Both strains were administered 500 ppm urethane in their drinking water for...
journal_title：Toxicologic pathology
pub_type： 杂志文章
doi：10.1080/01926230590908231
更新日期：2005-01-01 00:00:00
abstract：:Transgenic mouse strains offer the prospect of significant benefits in the in vivo assessment of carcinogenic potential. The European Regulatory Authorities have been supportive of their inclusion as one of the second-test options in the International Conference on Harmonization of Technical Requirements for the Regis...
journal_title：Toxicologic pathology
pub_type： 杂志文章,评审
doi：10.1080/01926230252824879
更新日期：2002-01-01 00:00:00
abstract：:High-resolution digitalizing of histology slides facilitates the development of computational alternatives to manual quantitation of features of interest. We developed a MATLAB-based quantitative histological analysis tool (QuHAnT) for the high-throughput assessment of distinguishable histological features. QuHAnT val...
journal_title：Toxicologic pathology
pub_type： 杂志文章
doi：10.1177/0192623314544379
更新日期：2015-04-01 00:00:00
