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Biomedical subjects

J E Dillberger

Publications and source records attributed to J E Dillberger.

At least 19 recordsLinked to original sources
PubMed1999

Immunogenicity of thrombopoietin mimetic peptide GW395058 in BALB/c mice and New Zealand white rabbits: evaluation of the potential for thrombopoietin neutralizing antibody production in man.

Administration of exogenous proteins and peptides as therapeutics carries with it the potential for immune system recognition and the development of neutralizing antibodies to endogenous regulatory proteins. PEGylation of proteins typically reduces their immunogenicity in vivo. GW395058 is a PEGylated peptide thrombopoietin receptor (TPOr) agonist being evaluated for the treatment of chemotherapy-induced thrombocytopenia. Although GW395058 shares no homology with TPO, it does compete with TPO for binding to a common receptor, and a similarity in local structure could result in shared epitopes. Thus GW395058 could elicit TPO-neutralizing antibodies. In this study, we evaluated the immunogenicity of GW395058 in mice, the potential of rabbit antibodies elicited by immunizations with the non-PEGylated parent peptide AF15705 to cross-react with recombinant human (rHu) TPO, and the potential of mouse anti-rHuTPO antibodies elicited by repeated dosing with rHuTPO to cross-react with AF15705. GW395058-dosed mice failed to produce antibodies to AF15705 or rHuTPO. Mouse anti-rHuTPO did not cross-react with AF15705 and rabbit anti-AF15705 antibodies failed to cross-react with rHuTPO. GW395058 caused no immune-mediated lesions in mice, but rHuTPO suppressed megakaryocytopoiesis and caused B-lymphocyte hyperplasia in lymphoid tissues consistent with antigenic stimulation. These data suggest that the potential for an immune response to GW395058 in man would be low.

Animals↗
PubMed1999

Pharmacokinetics and hematological effects of the PEGylated thrombopoietin peptide mimetic GW395058 in rats and monkeys after intravenous or subcutaneous administration.

GW395058, a potent PEGylated peptide human thrombopoietin receptor (HuTPOr) agonist in vitro, is being evaluated for the treatment of thrombocytopenia. GW395058 shares no sequence homology with TPO. In this report the pharmacokinetics and hematological effects of GW395058 in rats and monkeys are described. Doses eliciting thrombocytosis in rodents (2 or 10 microg/kg s.c.) produced insufficient plasma concentration data for pharmacokinetic parameter estimate calculations. At higher i.v. doses in rats (500, 1,000 or 2,000 microg/kg) serum t1/2 (half-life) values were >20 h, and the area under the concentration time curve increased proportionally with dose. In cynomolgus monkeys GW395058 plasma t1/2 values ranged from 37 to 68 h after s.c. or i.v. dosing, and similar values were observed in rhesus monkeys following s.c. dosing. Rat platelet counts increased following 2 (1.6-fold) or 10 microg/kg (fourfold) s.c. doses. Cynomolgus and rhesus monkey platelet counts did not change significantly at comparable s.c. doses, but did increase slightly (<twofold) in cynomolgus monkeys following a 25 microg/kg s.c. dose and twofold following a 100 microg/kg s.c. dose. Because the plasma t1/2 of GW395058 is long in mouse, rat, dog, and monkey, yet the dose required to double platelet levels in monkeys is 50-fold that required in rats, differences in hematological responses may be due to interspecies differences in the interaction of GW395058 with the TPOr.

Amino Acid Sequence↗
PubMed1994

Hemobartonella-like parasites in cynomolgus monkeys (Macaca fascicularis).

Red blood cell parasites were identified electron microscopically in five anemic adult female cynomolgus monkeys (Macaca fascicularis), two of which died during anemic episodes. Organisms typically were 0.3-0.5-micron round, oval, or reniform bodies on the surface or within vacuoles of erythrocytes. Based on their size, location in the erythrocyte, and internal ultrastructural features, organisms were classified as Hemobartonella-like. The relationship between the organisms and the anemias in these monkeys was unclear. This report adds rickettsial erythrocyte infections to the list of latent infections that can complicate research studies with cynomolgus monkeys.

Anaplasmataceae Infections↗
PubMed1993

Antioxidant MDL 29,311 prevents diabetes in nonobese diabetic and multiple low-dose STZ-injected mice.

Recent investigations suggest a role for antioxidants in preventing IDDM. MDL 29,311 (4,4'-[methylenebis(thio)]bis](1,1- dimethylethyl)]-phenol) is an analogue of the antioxidant probucol. Administered as a 1% dietary admixture to female nonobese diabetic mice from 4 to 24 wk of age, MDL reduced the prevalence of diabetes from 49 to 4% at 24 wk of age (n = 50-61/group). Discontinuation of treatment at 24 wk of age did not result in a rapid onset of diabetes. Probucol (1%) did not prevent diabetes. Initiating MDL treatment at 4 or 8 wk of age was more effective (19 and 17%, respectively, compared with 60% in control mice) than initiating treatment at 12 wk of age (30% diabetic; n = 28-35/group). A lower dose of MDL (0.1%), started at 4 wk of age, decreased the prevalence of diabetes to 36%. Histopathology indicated that MDL did not prevent insulitis. MDL (0.1%) also was evaluated in combination with immunosuppressants. Compared with control mice (65% diabetic), the combination of MDL and deflazacort was more effective (21% diabetic) than either agent alone (39% diabetic for MDL and 59% diabetic for deflazacort), whereas the effectiveness of MDL, cyclosporin, and MDL plus cyclosporin was similar (39, 38, and 34% diabetic, respectively). In another model of IDDM, the multiple-low-dose streptozocin-injected mouse, MDL (1%) also reduced the prevalence of diabetes when administered beginning 8 wk before streptozocin (55% diabetic vs. 100% of control mice; n = 20-25/group). Probucol (1%) was ineffective. MDL appears effective in preventing the onset of disease in two mouse models of IDDM.

Aging↗
PubMed1992

Prednisone is not a mouse carcinogen.

The carcinogenic potential of prednisone, a synthetic corticosteroid used as an anti-inflammatory and immunosuppressive agent, was investigated by feeding it to Crl:CD-1(ICR) mice (50/sex/dose) at doses of 0.25, 0.50, 1.0, and 5.0 mg/kg/day for 18 months. Prednisone did not significantly increase the incidence of neoplasms (p less than or equal to 0.05); on the contrary, it significantly decreased the incidence of hepatocellular tumors (p = 0.002 in males, p = 0.027 in females), male lacrimal/Harderian gland tumors (p = 0.05), female pulmonary adenomas (p = 0.047), female endothelial cell tumors (p = 0.035), and female lymphosarcomas (p = 0.02). This study suggests that long-term (lifetime) prednisone use does not increase cancer risk and may actually reduce it.

Animals↗
PubMed1990

Malignant transformation of human fibroblasts by a transfected N-ras oncogene.

The only ras oncogene as yet identified in cells from human fibrosarcomas is N-ras, but the relationship between N-ras oncogene expression and the malignant state of these cell lines is not known. To determine if expression of an N-ras oncogene causes human cells to become malignant, we transfected the N-ras oncogene from human leukemia cell line 8402, cloned into a high expression vector pSV N-ras, into MSU-1.1 cells, a nontumorigenic, infinite life span fibroblast cell strain with a normal morphology and a stable near-diploid karyotype. The transformants formed distinct foci composed of morphologically transformed cells. Cells from such foci expressed higher than normal levels of N-ras protein, exhibited growth factor independence, and formed large colonies in soft agar at a high frequency. Injection of progeny of these focus-derived cells s.c. into athymic mice resulted in progressively growing, invasive malignant tumors (round cell, spindle cell, or giant cell sarcomas) which reached a diameter of 6 mm in 3 to 4 weeks. Injection of focus-derived or tumor-derived cells i.v. resulted in tumors in various organs of the mice. The focus-derived cell strain tested, as well as the majority of the cells derived from the tumor it produced, exhibited the same near-diploid karyotype as the parental MSU-1.1 cells. Cells transfected with an N-ras oncogene that was expressed at a normal level formed only a single, indistinct focus, and cells from that focus were not malignant.

Animals↗
PubMed1990

Malignant transformation of an infinite life span human fibroblast cell strain by transfection with v-Ki-ras.

To determine if human fibroblasts can be transformed into malignant cells by transfection of a K-ras oncogene, we transfected the provirus of Kirsten murine sarcoma virus (v-Ki-ras) into an infinite life span human cell strain, MSU-1.1, which has a normal morphology, is not anchorage independent, and has a stable, near-diploid karyotype. The transfected populations gave rise to distinct foci composed of morphologically-altered cells. The cells from several independent foci were isolated, propagated, and assayed for anchorage independence and/or tumorigenicity. They formed large-sized colonies in soft agar at a high frequency. Cell strains derived from colonies isolated from agar as well as focus-derived cell strains were injected subcutaneously into athymic mice to test for tumorigenicity. One cell strain yielded myxoid fibromas, the rest produced well-differentiated, progressively-growing, invasive, myxoid or spindle cell sarcomas. The karyotype of each of the cell strains tested, including cell strains derived from tumors, was identical to that of non-transfected MSU-1.1 cells. Two focus-derived strains, and two cell strains derived from sarcomas produced from them, were tested and shown by DNA and RNA hybridization to contain and express the v-Ki-ras oncogene. Radioimmunoprecipitation analysis showed that these strains expressed ras-specific p21 products not found in non-transfected MSU.1.1 cells. When injected intraperitoneally, a cell strain derived from a myxoid tumor gave rise to invasive myxoid tumors at various sites in the body. The same cell strain gave rise to invasive spindle cell sarcomas when injected into the tail vein of the animals.

Blotting, Northern↗
PubMed1989

Neoplasia in ferrets: eleven cases with a review.

Records from a veterinary diagnostic laboratory in south Florida, U.S.A. were reviewed for cases of neoplasia in pet ferrets. Twelve ferret tumours were received over a four-year period; one case, a ferret with lymphocytic leukaemia and multi-organ involvement, had been reported previously. The other eleven tumours were: two chordomas of the tail, two sebaceous adenomas of the skin, a sebaceous epithelioma of the skin, a cutaneous mastocytoma, a malignant fibrous histiocytoma from the eyelid, a malignant mesenchymoma and an undifferentiated sarcoma from the dorsal abdominal cavity, a leiomyosarcoma found unattached in the abdominal cavity and an interstitial cell tumour of the testicle. A review of the literature yielded reports of 83 other tumours in domestic ferrets, black-footed ferrets and European polecats. Of the 95 ferret tumours, 46 were considered malignant. Tumours occurred in all organ systems except the respiratory tract and central nervous system. Affected ferrets ranged in age from 209 days to 12 years. The most frequently occurring tumours were ovarian stromal tumours (24 of 95), haemangiomas/haemangio-sarcomas (15 of 95). This information indicates that, contrary to previous opinion, ferrets appear to be subject to a similar incidence and variety of tumours as other animals.

Animals↗
PubMed1988

Protothecosis in two cats.

Protothecosis was diagnosed in 2 cats from Florida with nodular skin lesions. Microscopically, lesions were composed of macrophages and multinucleated giant cells arranged in solid sheets in the dermis and subcutis. In both cats, characteristic algal endospores identified as Prototheca wickerhamii were observed within the cytoplasm of infiltrating cells.

Animals↗
PubMed1987

A malignant nephroblastoma in an aged fox (Fennecus zerda).

A malignant nephroblastoma with pulmonary metastasis which was found at necropsy in an old fox is described. This is the first report of such a tumour in a fox. Nephroblastoma is rare in the family Canidae and usually occurs in young individuals. The presence of a tumour arising from embryonal tissue in an aged animal raises questions about the genesis and behaviour of this tumour. The tumour may have contributed to the animal's congestive heart failure as a result of the generalized pulmonary involvement, an erythropoietin-induced polycythaemia, or increased peripheral resistance via the renin-angiotensin system.

Animals↗
PubMed1986

Topical fluorouracil. II. Postoperative administration in an animal model of glaucoma filtering surgery.

Unilateral posterior lip sclerectomies were performed in ten owl monkeys. Five milligrams of fluorouracil was injected subconjunctivally in each operated eye immediately after surgery. Three drops (approximately 2.4 mg/drop) of fluorouracil were instilled ten minutes apart in each operated eye twice daily on postoperative days 1 through 7 and once daily on postoperative days 8 through 15, 17, 19, and 21. One monkey died on the seventh postoperative day; its death could not be attributed to systemic fluorouracil toxicity. All of the operated eyes had filtering blebs after the full course of fluorouracil, but seven also had corneal epithelial defects. By the seventh postoperative week, two of the operated eyes manifested moderately severe corneal opacification. Ten weeks postoperatively, the electroretinographic a- and b-wave amplitudes averaged 17% and 12% less, respectively, in the seven operated eyes without clinically significant corneal opacification than in the unoperated fellow eyes. Only two eyes had blebs after the 12th postoperative week. Histopathologic examination was performed on five eyes, of which only two revealed patent sclerostomies. Although topical fluorouracil appears to delay bleb scarring, the corneal findings suggest that it may be more toxic than subconjunctival fluorouracil.

Administration, Topical↗
PubMed1986

Focal mucinosis in dogs: seven cases and review of cutaneous mucinoses of man and animals.

Seven dogs had one or more asymptomatic nodules, papules, or plaques on the skin or oral mucosa. The primary histologic feature was the accumulation of excess mucin within the dermis or submucosa. Based upon the clinical presentation and the histopathologic changes, it was proposed that these lesions represent the canine analogue of focal mucinosis in man, and that the same name be applied to the lesion in dogs. The criteria for the diagnosis of focal mucinosis were: (1) the presence of a single (rarely multiple) papule, nodule, or plaque which may be firm, rubbery, or soft, (2) the accumulation of mucin which disrupts and separates collagen fibers, (3) mild to extensive fibroblast proliferation, and (4) a mild mononuclear cell infiltration. The mucinoses of man and animals were reviewed.

Animals↗
PubMed1985

Polycystic kidneys in a ferret.

Polycystic kidneys were found at necropsy in an adult ferret with a history of seizures and a palpable abdominal mass. Both kidneys contained numerous fluid-filled cysts of various sizes. The ferret may provide an animal model for the study of polycystic disease in man.

Animals↗