Abstract:
:Fusion of biologic therapeutics to hyaluronic acid binding proteins, such as the link domain (LD) of Tumor necrosis factor (TNF)-Stimulated Gene-6 (TSG-6), is expected to increase vitreous residence time following intravitreal injection and provide for long-acting delivery. The toxicity of a single intravitreal dose of free TSG-6-LD and fusion proteins of TSG-6-LD and a nonbinding rabbit antibody fragment (RabFab) were assessed in New Zealand White rabbits. Animals administered free TSG-6-LD exhibited extensive lens opacities and variable retinal vascular attenuation, correlated with microscopic findings of lens and retinal degeneration. Similar but less severe findings were present in animals dosed with the RabFab-TSG-6-LD fusion proteins. In-life ocular inflammation was noted in all animals from 7-days postdose and was associated with high anti-RabFab antibody titers in animals administered fusion proteins. Inflammation and retinal degeneration were multifocally associated with evidence of retinal detachment, and hypertrophy and migration of vimentin, glial fibrillary acidic protein, and glutamine synthetase positive Müller cells to the outer nuclear layer. Further assessment of alternative hyaluronic acid binding protein fusions should consider the potential for retinal degeneration and enhanced immune responses early in development.
journal_name
Toxicol Patholjournal_title
Toxicologic pathologyauthors
Laing ST,Tassew N,Tesar D,Wang Y,Crowell SR,Gray J,Kwong M,Loyet KM,Andaya R,Kusi A,Kelley RFdoi
10.1177/0192623320969124subject
Has Abstractpub_date
2020-12-21 00:00:00pages
192623320969124eissn
0192-6233issn
1533-1601pub_type
杂志文章abstract::Seventeen mesotheliomas from 395 untreated male Fischer 344/DuCrj rats were studied by light and electron microscopy to define the morphological characteristics of the tumors. In 16 out of 17 rats, mesotheliomas were observed in the abdominal and/or scrotal sac, and the other one was localized on the pleura. Grossly, ...
journal_title:Toxicologic pathology
pub_type: 杂志文章
doi:10.1177/019262338701500205
更新日期:1987-01-01 00:00:00
abstract::Analgesics and nonsteroidal anti-inflammatory drugs (NSAIDs) are well recognized as a major class of therapeutic agent that causes renal papillary necrosis (RPN). Over the last decade a broad spectrum of other therapeutic agents and many chemicals have also been reported that have the potential to cause this lesion in...
journal_title:Toxicologic pathology
pub_type: 杂志文章,评审
doi:10.1177/019262339802600110
更新日期:1998-01-01 00:00:00
abstract::The histologic effect of 400 mg/M2/day of hydrocortisone, given alternatively from day 7 to day 19 after birth, was studied on the spleen of the immunologically immature rat. Two days after the cessation of treatment, the periarteriolar lymphatic sheaths were found to be largely depleted of small lymphocytes. Immunope...
journal_title:Toxicologic pathology
pub_type: 杂志文章
doi:10.1177/019262339302100406
更新日期:1993-01-01 00:00:00
abstract::There is increased interest to use minipigs in ocular toxicology studies due to their anatomical similarities with human eyes and as a substitute for nonhuman primates. This requires adaptation of enhanced optical coherence tomography (OCT) techniques and of ocular relevant immunohistochemistry (IHC) or in situ hybrid...
journal_title:Toxicologic pathology
pub_type: 杂志文章
doi:10.1177/0192623315615553
更新日期:2016-04-01 00:00:00
abstract::Results of early nonclinical "General Toxicology" studies are used to set a safe starting dose for first-in-human (FIH) clinical trials. In FIH trials, the research subjects are typically healthy volunteers who have little to gain but much to lose if a trial goes wrong. With that in mind, good laboratory practice regu...
journal_title:Toxicologic pathology
pub_type: 杂志文章
doi:10.1177/0192623313506878
更新日期:2014-01-01 00:00:00
abstract::The spleen contains hematopoietic and lymphoid elements, is a primary site of extramedullary hematopoiesis, and removes degenerate and aged red blood cells as well as particulate materials and circulating bacteria from the blood supply. Lesions of this important component of the immune system may center on the red pul...
journal_title:Toxicologic pathology
pub_type: 杂志文章,评审
doi:10.1080/01926230600867750
更新日期:2006-01-01 00:00:00
abstract::In the constantly evolving field of toxicologic pathology, a pathologist's career is often characterized by multiple career transitions. However, these transitions can be challenging and/or overwhelming and may require a shift in focus, strategic approach, and acquisition of new skills and expertise. In order to provi...
journal_title:Toxicologic pathology
pub_type: 杂志文章
doi:10.1177/0192623317736299
更新日期:2017-10-01 00:00:00
abstract::Zibotentan, an endothelin-A receptor antagonist, has been used in the treatment of various cardiovascular disorders and neoplasia. Castrated athymic nude mice receiving zibotentan for a preclinical xenograft efficacy study experienced weight loss, gastrointestinal bloat, and the presence of an audible respiratory clic...
journal_title:Toxicologic pathology
pub_type: 杂志文章
doi:10.1177/0192623318816295
更新日期:2019-02-01 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 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 regulatio...
journal_title:Toxicologic pathology
pub_type: 传,历史文章,杂志文章,评审
doi:10.1177/0192623309345871
更新日期:2009-10-01 00:00:00
abstract::The microbiome is increasingly recognized as a critical component in human development, health, and disease. Its relevance to toxicology and pharmacology involves challenges to current concepts related to absorption, metabolism, gene:environment, and pathways of response. Framing testable hypotheses for experimental a...
journal_title:Toxicologic pathology
pub_type: 杂志文章,评审
doi:10.1177/0192623316672073
更新日期:2017-01-01 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::Subacute inhalation study (1 week or 2 weeks) is an important process for screening out inhaled compounds causing lung irritation. To investigate whether the lung weight can be used as an indicator for acute lung injury, we have analyzed retrospectively the lung weight data from 30 studies in rats exposed to dry powde...
journal_title:Toxicologic pathology
pub_type: 杂志文章
doi:10.1177/0192623312470763
更新日期:2013-08-01 00:00:00
abstract::Oxymetholone has been identified as a suspected nongenotoxic carcinogen and has recently completed testing in a conventional National Toxicology Program (NTP) 2-yr rodent bioassay program. As a synthetic androgen with a limited historical database in toxicology, oxymetholone is an ideal candidate for prospective exami...
journal_title:Toxicologic pathology
pub_type: 评论,杂志文章
doi:10.1177/019262339902700503
更新日期:1999-09-01 00:00:00
abstract::The renal toxicity of harman and norharman, administered for 2 or 4 weeks at dietary levels of 1,000, 500, or 0 parts per million (ppm), was investigated in 6-week-old male F344/DuCrj rats. Although rats fed 1,000 ppm harman or norharman, but not the 500 ppm level, demonstrated marked body weight retardation from 1 we...
journal_title:Toxicologic pathology
pub_type: 杂志文章
doi:10.1177/019262339202000206
更新日期:1992-01-01 00:00:00
abstract::A variety of phenotypic cellular changes emerge in the liver of different species prior to the appearance of hepatocellular adenomas and carcinomas induced by carcinogenic agents (chemicals, radiation, hepadna viruses) or develop "spontaneously." Foci of altered hepatocytes have been studied most extensively in rats t...
journal_title:Toxicologic pathology
pub_type: 杂志文章,评审
doi:10.1177/0192623389017004107
更新日期:1989-01-01 00:00:00
abstract::Many antisense oligonucleotides (ASOs) from several classes of molecules are currently in drug development. Despite over 20 years of pharmaceutical research, few ASOs have been marketed due to problems with clinical efficacy or preclinical toxicologic challenges. However, a number of recent developments have renewed i...
journal_title:Toxicologic pathology
pub_type: 杂志文章,评审
doi:10.1177/0192623314551840
更新日期:2015-01-01 00:00:00
abstract::Progressive renal interstitial fibrosis occurs following tissue injury, resulting in chronic renal failure. In the fibrogenesis, macrophages are speculated to induce myofibroblasts producing matrix protein. The kinetics of these cells in renal fibrosis induced in rats by repeated injection of cisplatin (CDDP) (2 mg/kg...
journal_title:Toxicologic pathology
pub_type: 杂志文章
doi:10.1177/019262339602400208
更新日期:1996-03-01 00:00:00
abstract::The lung is a target organ for the toxic effects of several chemical agents, including natural products, industrial chemicals, pesticides, environmental agents, and occasionally, drugs. Factors that establish the lung as a target organ include selective tissue exposure, high tissue oxygenation, and the presence of bio...
journal_title:Toxicologic pathology
pub_type: 杂志文章,评审
doi:10.1177/019262339101900415
更新日期:1991-01-01 00:00:00
abstract::Normal retina and its cell layers are essential for processing visual stimuli, and loss of its integrity has been documented in many disease processes. The numbers and the axonal processes of retinal ganglion cells are reduced substantially in glaucoma, leading to vision loss and blindness. Similarly, selective loss o...
journal_title:Toxicologic pathology
pub_type: 杂志文章
doi:10.1177/0192623320976375
更新日期:2020-12-31 00:00:00
abstract::To clarify the cell of origin of granular cell tumors in the rat brain, light and/or electron microscopic examinations were performed on 40 cases of spontaneous meningeal tumors in Wistar (Jcl: Wistar) rats. The meningeal tumors were histologically subclassified into 3 types: meningothelial meningiomas (MMs), 3 cases;...
journal_title:Toxicologic pathology
pub_type: 杂志文章
doi:10.1177/019262339702500211
更新日期:1997-03-01 00:00:00
abstract::A number of factors related to study design have the potential to impact clinical pathology test results during the conduct of nonclinical safety studies. A thorough understanding of these factors is paramount in drawing accurate conclusions from clinical pathology data generated during such studies, particularly when...
journal_title:Toxicologic pathology
pub_type: 杂志文章,评审
doi:10.1177/0192623316677066
更新日期:2017-02-01 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 nondopaminergic antipsychotic agent, 5-ethyl-1,3,8-trimethyl-1H-imidazo]1,2-c]pyrazolo[3,4-e]pyrimidine (TIPP; PD 112488), has been tested for potential toxicity in rats. As part of a preclinical safety evaluation, 10 Wistar rats per sex were administered TIPP as a dietary admixture, receiving doses of 0, 5, 10, 20,...
journal_title:Toxicologic pathology
pub_type: 杂志文章
doi:10.1177/019262339402200106
更新日期:1994-01-01 00:00:00
abstract::A rat liver foci bioassay (RLFB) based on an initiation-promotion protocol employing preneoplastic foci of altered hepatocytes (FAH) as an endpoint, was prevalidated in 5 different laboratories. FAH were identified by immunohistochemical demonstration of glutathione-S-transferase (placental form, GSTP) and by staining...
journal_title:Toxicologic pathology
pub_type: 杂志文章
doi:10.1080/01926230390173888
更新日期:2003-01-01 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::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::The expression of specific cytokeratin (CK) polypeptide patterns is a sensitive marker of the cytoskeletal differentiation of epithelial cells. We developed an immunohistochemical method to assess CK expression patterns in the rat respiratory tract using serial paraffin-embedded sections from the nasal cavity, trachea...
journal_title:Toxicologic pathology
pub_type: 杂志文章
doi:10.1177/019262339802600308
更新日期:1998-05-01 00:00:00
abstract::Parenteral administration of recombinant hematopoietic growth factors has been sporadically associated with cutaneous complications, including injection site reactions in humans and nonhuman primates. In this study, subcutaneous injection sites were evaluated from 12 cynomolgus monkeys administered a recombinant human...
journal_title:Toxicologic pathology
pub_type: 杂志文章
doi:10.1177/019262339602400401
更新日期:1996-07-01 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