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Biomedical subjects

J M Ward

Publications and source records attributed to J M Ward.

At least 289 records · Page 16Linked to original sources
PubMed1985

Proliferative lesions of the glandular stomach and liver in F344 rats fed diets containing Aroclor 1254.

Aroclor 1254 was fed to groups of 24 male and 24 female F344 rats, from 7 weeks of age, at dietary concentrations of 25, 50 and 100 ppm for up to 105 weeks. There was a dose- related depression of body weight gain for both sexes and decrease in survival for male rats. Histologically, an increased incidence of gastric intestinal metaplasia and adenocarcinoma was found in both sexes. Hepatocellular adenomas, carcinomas, and eosinophilic and vacuolated hepatocellular foci were usually found in dosed rats only. The number of these foci per unit area of liver was significantly increased in dosed rats, although eosinophilic foci were only found in rats exposed to Aroclor 1254. Basophilic hepatocellular foci were found in similar numbers per square centimeter of liver in controls and treated rats. This finding suggested that eosinophilic hepatocellular foci and tumors arose de novo rather than from the naturally occurring basophilic foci. The appearance of unique, potentially preneoplastic lesions and tumors in the liver and stomach in dosed rats which do not usually occur spontaneously in control rats would support the hypothesis that Aroclor 1254 induced or initiated these unique lesions de novo rather than promoted the growth of any naturally occurring lesions. Nonneoplastic hepatic lesions included degenerative hepatocellular changes and aggregates of macrophages with crystalline cytoplasmic structures and pigment granules.

Animals↗
PubMed1985

Preventive and enhancing effects of retinoids on the development of naturally occurring tumors of skin, prostate gland, and endocrine pancreas in aged male ACI/segHapBR rats.

The effects of dietary retinoids on the development of naturally occurring tumors in retired breeder male ACI/segHapBR rats were investigated. Groups of rats (21-25 mo of age, an age when early neoplasms first appear and tumor incidences are generally low) were fed diets containing 1 of 3 retinoids--all-trans-N-4-(4-hydroxyphenyl)retinamide (4-HPR), 783 mg/kg diet; all-trans-N-(4-pivaloyloxyphenyl)retinamide (4-PPR), 951 mg/kg; or all-trans-4-N-(2-hydroxyethyl)retinamide (2-HER), 687 mg/kg--or control diet for up to 54 weeks (average, 33 wk). Rats were maintained until less than 20% remained and the experiment was terminated. Contributing causes of death were determined, and a complete necropsy was performed for each rat. There was no difference between the retinoid-treated rats and control rats in the average age at death (30-31 mo) or in the average experimental survival time (29-35 wk), in the proportions of tumor-bearing rats (95.6-100%), or in the average number of organs with tumor per rat (2.1-2.5). The incidences of pancreatic islet cell adenoma and skin tumors were significantly different between control and some retinoid-treated groups. 4-PPR and 2-HER significantly enhanced pancreatic islet cell adenoma yields (P less than .025 and 0.05, respectively) whereas 4-HPR significantly inhibited epithelial and connective tissue skin tumor yields (P less than .025). Incidences of skin and prostate tumors were lower than in controls, but not significantly, in rats receiving 4-PPR and 2-HER. Most of the islet cell adenomas were shown, by avidin-biotin-peroxidase complex immunocytochemistry, to be insulinomas. 4-HPR would seem to be the most effective retinoid in the group, inasmuch as it prevented skin tumor development, may have slightly decreased the incidence of prostate tumors, and did not enhance islet cell tumor incidence.

Adenoma, Islet Cell↗
PubMed1985

Comparative tumor-promoting activities of phenobarbital, amobarbital, barbital sodium, and barbituric acid on livers and other organs of male F344/NCr rats following initiation with N-nitrosodiethylamine.

Tumor-promoting abilities of four barbiturates, phenobarbital [(PB) CAS: 50-06-6], amobarbital [(AB) CAS: 57-43-2], barbital sodium [(BB) CAS: 144-02-5], and barbituric acid [(BA) CAS: 67-52-7], on the development of neoplasms in livers and other organs of rats following initiation with N-nitrosodiethylamine [(DENA) CAS: 55-18-5] were compared. Four-week-old F344/NCr male rats were given a single ip injection of 75 mg DENA/kg body weight. Beginning 2 weeks later, they were given either tap water (group 1) or drinking water containing 500 ppm of PB (group 2), the sodium salt of BB (group 3), AB (group 4), or BA (group 5) for the remaining experimental period. Control groups (groups 6-10) received an ip injection of saline alone and 2 weeks later were given either tap water or drinking water containing barbiturates as listed above. Animals were sacrificed at either 52 weeks or 78 weeks. None of the barbiturates altered the growth and survival of animals. PB and BB increased liver weights and significantly enhanced the development of hepatocellular foci and hepatocellular adenomas at 52 weeks and hepatocellular foci, hepatocellular adenomas, and trabecular carcinomas at 78 weeks in DENA-treated rats. No such enhancing effects were observed with AB or BA. PB or BB did not significantly enhance the incidence of nonhepatic tumors at 52 weeks. However, at 78 weeks BB significantly enhanced the development of renal tubular adenomas and carcinomas, while PB enhanced the development of thyroid follicular cell neoplasms in DENA-treated rats. These results clearly showed that barbiturates exhibited structure-promoting activity relationships and that their promoting abilities were not restricted to liver alone. Substitution of both hydrogen atoms at the C-5 position of the pyrimidine ring by alkyl or aryl groups appears to be essential but not sufficient for tumor-promoting activity of barbiturates.

Amobarbital↗
PubMed1985

Immunocytochemical localization of the surfactant apoprotein and Clara cell antigen in chemically induced and naturally occurring pulmonary neoplasms of mice.

The localization of surfactant apoprotein (SAP) and the Clara cell antigen(s) (CCA) was studied in naturally occurring and experimentally induced pulmonary hyperplasias and neoplasms by avidin-biotin peroxidase complex (ABC) immunocytochemistry. Lungs of B6C3F1 and A strain mice with naturally occurring lesions, B6C3F1 mice given injections of N-nitrosodiethylamine (DEN), BALB/c nu/nu or nu/+ mice exposed transplacentally on Day 16 of gestation to ethylnitrosourea (ENU), or BALB/c nu/+ mice exposed to ENU at 8-12 weeks of age were preserved in formalin or Bouin's fixative. After ABC immunocytochemistry, SAP was found in the cytoplasm of normal alveolar Type II cells; in the majority of cells in focal alveolar and solid hyperplasias originating in peribronchiolar or peripheral locations; and in solid, tubular, papillary, and mixed adenomas and carcinomas. The larger mixed-pattern neoplasms and small or large tubular neoplasms usually had the least number of cells with SAP. The majority of large papillary adenomas and carcinomas in BALB/c mice exposed to ENU and in untreated A strain mice contained SAP in the nuclei of many neoplastic cells but only in the cytoplasm of a few neoplastic cells. CCA was found in normal Clara cells of bronchi and bronchioles but not in any hyperplastic or neoplastic lesion of any mouse studied. This study provided immunocytochemical evidence that the vast majority of naturally occurring and experimentally induced pulmonary neoplasms of mice are alveolar Type II cell adenomas and carcinomas.

Adenoma↗
PubMed1985

Immunocytochemical and morphological evidence for the origin of N-nitrosomethylurea-induced and naturally occurring primary lung tumors in F344/NCr rats.

Naturally occurring and N-nitrosomethylurea-induced lung tumors were studied in male F344/NCr rats by sequential histological, electron microscopic, and immunohistochemical methods. Rats were given one injection at 6 weeks of age of N-nitrosomethylurea at a dosage level of 41.2 mg/kg body weight i.v. Groups of rats were sacrificed at 20, 33, and 52 weeks, while some were sacrificed while moribund. Nine lung tumors from aged F344/NCr male rats were also studied. For determining localization of pulmonary antigens, sections of lungs were stained by the avidin-biotin-peroxidase complex immunocytochemical technique using antibodies to rat surfactant apoprotein or rat Clara cell antigen. At 20 weeks, in rats receiving N-nitrosomethylurea, focal alveolar type II cell hyperplasia, adenoma in focal alveolar type II cell hyperplasia, and adenoma were found in 15 (100%), 1 (7%), and 2 (13%) of 15 rats, respectively. At 33 weeks, there were 19 rats (95%) with focal alveolar type II cell hyperplasias, 10 rats (50%) with adenoma in focal alveolar type II cell hyperplasia, and 2 rats (10%) with adenomas in 20 rats. In 53 rats allowed to live up to 52 weeks, there were 10 (19%) adenomas and 3 (6%) carcinomas, as well as 49 (92%) rats with focal hyperplasia and 31 (58%) with adenomas in focal type II cell hyperplasia. Rat surfactant apoprotein was found in the cytoplasm of normal alveolar type II cells and the majority of cells in focal alveolar type II cell hyperplasias, adenomas in hyperplastic lesions, adenomas, and carcinomas. The ultrastructure of these lesions supported immunocytochemical findings with evidence of lamellar bodies. All nine naturally occurring lung tumors studied contained rat surfactant apoprotein. Rat Clara cell antigen was found, however, only focally within one adenoma induced by N-nitrosomethylurea and one adenoma in a hyperplastic lesion, and also focally in three neoplasms which occurred naturally. This study provided morphological, immunohistochemical, and ultrastructural evidence that the vast majority of N-nitrosomethylurea-induced and naturally occurring pulmonary neoplasms of F344 rats are alveolar type II cell adenomas and carcinomas and that a portion of these tumors arise within focal alveolar type II cell hyperplasias.

Animals↗
PubMed1984

Di(2-ethylhexyl)phthalate but not phenobarbital promotes N-nitrosodiethylamine-initiated hepatocellular proliferative lesions after short-term exposure in male B6C3F1 mice.

The differential effects of short- or long-term exposure to the liver tumor promoters di(2-ethylhexyl)phthalate (DEHP) or phenobarbital (PB) were studied in male B6C3F1 mice. Mice were injected intraperitoneally (i.p.) at 4 weeks of age with N-nitrosodiethylamine (DEN) at a dosage of 80 mg/kg. At 5 weeks of age, the mice were fed diets containing PB or DEHP for periods of from 1 to 168 days and killed at 168 or 252 days. When DEHP was fed at a dietary level of 3000 ppm for 28, 84, or 168 days, or PB was fed in the water at 500 ppm for 168 days, there were significantly increased incidences of mice with focal hepatocellular proliferative lesions (FHPL) as compared with those in mice receiving DEN alone. There was no significant promotion of FHPL when DEHP was fed for 1 or 7 days or when PB was fed for 1, 7, 28, or 84 days. Thus, DEHP was an effective promoter after only 28, 84, or 168 days exposure whereas PB required 168 days of continuous exposure for a promotive effect to be evident.

Animals↗
PubMed1984

Inhibition by phenobarbital and lack of effect of amobarbital on the development of liver tumors induced by N-nitrosodiethylamine in juvenile B6C3F1 mice.

The effects of phenobarbital (PB) and amobarbital (AB) on the rate of development of hepatocarcinogenesis induced by N-nitrosodiethylamine (DEN) were studied in mice. Groups of 40 B6C3F1 male mice were injected i.p. at 15 days of age with 5 micrograms DEN/g body wt. Beginning at 4 weeks of age, DEN treated groups were given either normal drinking water or water containing either 0.05% PB or AB for up to 36 weeks. DEN alone induced multiple focal hepatic lesions including hepatocellular foci, hepatocellular adenomas and trabecular carcinomas. Subsequent exposure to PB had a suppressing effect on DEN-induced hepatocarcinogenesis. Hepatocellular foci in PB-exposed mice were significantly smaller in size (area) and fewer in number throughout the study. Also, PB treatment either prolonged the latency period or significantly slowed the rate at which hepatocellular tumors developed in these mice. No such effects were seen in AB-exposed mice; AB neither inhibited nor promoted the development of focal hepatic lesions in DEN-pretreated mice. Possible mechanisms responsible for the inhibition of DEN-induced hepatocarcinogenesis include the feminizing effects of perinatal administration of PB.

Adenocarcinoma↗
PubMed1984

The early stage of large granular lymphocyte leukemia in the F344 rat.

In the early stages of large granular lymphocyte leukemia of F344 rats, splenic congestion and lymphocytic depletion of the splenic white pulp are the most significant and consistent histologic findings. The diagnosis of early leukemia was confirmed by immunocytochemical demonstration that the cell surface of leukemic large granular lymphocytes reacted with OX-8 monoclonal antibodies and by transplantation of the disease at early stages to healthy weanling rats.

Animals↗
PubMed1984

Papovaviral sialoadenitis in athymic nude rats.

A wasting disease was found in 32 athymic nude rats. The rats had parotid sialoadenitis with intranuclear inclusion bodies in ductal and acinar epithelial cells. Other common lesions included bronchitis, bronchiolitis and secondary bacterial pneumonia. Less commonly, rhinitis and Harderian adenitis were seen. Intranuclear inclusions were also seen in bronchial epithelium of 1 rat, Harderian gland acini of 1 rat and laryngeal glands of 2 rats. Viral particles, averaging 45 nm in diameter, sometimes in crystalline arrays, were found in the nucleus of parotid epithelial cells. By the use of the avidin-biotin-peroxidase complex (ABC) immunoperoxidase technique, antibodies to disrupted SV40 virus (the group specific antigen of the polyomavirus (miopapovavirus) genus of the papovavirus family) reacted with intranuclear inclusions and cytoplasm of parotid epithelium and inclusions in lung and Harderian gland. The viral antigen did not cross react with antibodies to mouse polyoma, mouse K or disrupted bovine papilloma viruses.

Animals↗
PubMed1984

A comparison of the avidin-biotin-peroxidase complex (ABC) and peroxidase-anti-peroxidase (PAP) immunocytochemical techniques for demonstrating Sendai virus infection in fixed tissue specimens.

Mice were infected with Sendai virus and killed 8 days later. Lungs were removed and perfused with ethanol, 10% neutral formalin, Bouin's, B-5, or Zenker's fixatives. Tissues were dehydrated, embedded in paraffin, sectioned and stained for the presence of Sendai virus using the avidin-biotin-peroxidase-complex (ABC) and peroxidase antiperoxidase (PAP) immunocytochemical techniques. Results of these techniques were compared. The ABC technique was more sensitive than the PAP. Sendai antigen was demonstrated by the ABC technique in lung tissue fixed with any fixative, whereas antigen could be demonstrated with consistency only in ethanol-fixed lung by the PAP technique. Trypsin treatment of lung prior to immunoperoxidase treatment failed to enhance staining with either technique and actually caused a decrease in staining in ethanol, B-5 and Zenker's-fixed specimens.

Animals↗
PubMed1984

Natural killer activity in the rat. III. Characterization of transplantable large granular lymphocyte (LGL) leukemias in the F344 rat.

Six transplantable large granular lymphocyte (LGL) tumor lines in F344 rats were examined for natural killer (NK) and antibody-dependent cell-mediated cytotoxicity. Tumor cells from all six lines were highly cytotoxic, even at low effector to target ratios, when tested against NK-susceptible targets, but were unreactive against an NK-resistant target (C58NT)D) and a macrophage-susceptible target (P815). Three lines showed significant levels of lysis against antibody-coated tumor cells. After in vivo transplantation, the levels of cytotoxicity steadily increased in three lines and decreased in one. The cytotoxic activity of one line (RNK-16) remained high through 12 transplant generations. Tumor cells injected i.p. spread via the lymphatics to regional lymph nodes, mediastinal nodes, blood, and eventually the bone marrow. Leukemia occurred concurrently with organ enlargement and increased levels of NK. Studies in (F344 X W/Fu)F1 rats clearly demonstrated that the cytotoxic cells from leukemic animals were the transplanted tumor cells themselves and not merely the activation of normal host LGL. These results demonstrate that naturally occurring, transplantable LGL leukemias are an easily obtainable and excellent source of materials for those studies requiring a large number of functionally active LGL.

Animals↗
PubMed1984

A sequential study of methapyrilene hydrochloride-induced liver carcinogenesis in male F344 rats.

Methapyrilene hydrochloride [2-[2-(dimethylamino)-ethyl)-2-thenylamino)pyridine monohydrochloride (CAS: 135-23-9)]-induced hepatocarcinogenesis was studied in male F344/NCr rats by sequential histologic, histochemical, and biologic methods. Methapyrilene hydrochloride was administered in the feed to rats at a concentration of 1,000 ppm for periods up to 89 weeks. Groups of rats were killed after 5, 10, 15, 29, 40, or 73 weeks of ingesting the carcinogen. Another group was allowed to live out their life-span. Hepatocellular eosinophilic foci and adenomas were seen after 10 and 15 weeks, respectively. Basophilic foci and adenomas were found after 29 and 40 weeks, respectively. Hepatocellular carcinomas developed in 5 of 10 rats at week 40, in 3 of 5 rats at week 73, and in 19 of 19 rats that lived out their life-span. Carcinomas arose within adenomas or as small in situ carcinomas. The histologic types included trabecular, adenocarcinoma, mixed, and solid poorly differentiated hepatocellular carcinomas. Eleven of the mixed and solid poorly differentiated carcinomas metastasized to the lung. Solid poorly differentiated hepatocellular carcinomas grew upon transplantation to the mammary fat pad of weanling F344 rats. Cholangiocarcinomas were found in 7 of 19 rats only in the life-span group. Mucous cholangiofibrosis was seen in all rats after 15 weeks. With the use of Regaud's mitochondrial stain, an increased cellular density of mitochondria was seen in some hepatocytes of peripheral and central lobular areas and in some hepatocellular carcinoma cells, but not in cells in many of the adenomas and foci. Cellular alpha-fetoprotein was found by immunoperoxidase staining in portions of hepatocellular carcinomas, but not in foci, adenomas, and nonneoplastic areas. The majority of hepatocytes in foci, adenomas, and hepatocellular carcinomas contained gamma-glutamyl transpeptidase. The findings suggest that multiple pathways may be followed in the development of methapyrilene-induced liver cancer that are similar to those found in rats exposed to many other hepatic carcinogens.

Aminopyridines↗
PubMed1984

Splenic fibrosis and sarcomas in F344 rats fed diets containing aniline hydrochloride, p-chloroaniline, azobenzene, o-toluidine hydrochloride, 4,4'-sulfonyldianiline, or D & C red No. 9.

In six carcinogenicity bioassays, male and female F344 rats were fed diets containing aniline hydrochloride (CAS: 142-04-1; hydrochloride benzenamide), p-chloroaniline (CAS: 106-47-8), azobenzene (CAS: 103-33-3), o-toluidine hydrochloride (CAS: 636-21-5), dapsone (CAS: 80-08-0; 4,4'-sulfonyldianiline), or D & C red No. 9 [CAS: D85500000; 5-chloro-2-[2-hydroxy-1-naphthalenyl)azo)-4-methylbenzenesulfon ic acid, barium salt]. The rats, from 6 weeks to 2 years old, were given the compounds at two dose levels, the estimated maximum tolerated dose and one-half that dose. In all six bioassays, dose-dependent incidences of splenic sarcomas and fibrosis were seen, with the highest incidences in male rats. Fibrosis occurred in the splenic parenchyma and/or the capsule. Fatty infiltration also was seen in the spleen. Sarcomas appeared to arise in the splenic red pulp or splenic capsule, usually in association with areas of parenchymal and capsular fibrosis and pigmentation. Larger tumors metastasized to the peritoneal cavity and abdominal organs. In some rats there was marked osseous metaplasia when the primary tumor metastasized to peritoneal surfaces. Other, less common, splenic neoplasms included hemangiosarcoma and hemangiopericytoma. Some rats had such extensive peritoneal involvement that the site of origin of their sarcoma was difficult to determine.

Aniline Compounds↗
PubMed1984

Promotion of N-methyl-N-nitrosourea-induced thyroid tumors by iodine deficiency in F344/NCr rats.

Six-week-old male F344 rats were each given an injection once iv of N-methyl-N-nitrosourea [(MNU) CAS: 684-93-5] at a dose of 41.2 mg/kg body weight. Two weeks later, groups of rats were placed on iodine-deficient (ID) or iodine-adequate (IA) diets and then sacrificed at 20 and 33 weeks. Other groups received ID or IA diets without MNU. For localizing thyroid-stimulating hormone (TSH) and prolactin, sections of pituitary glands were stained by the avidin-biotin-peroxidase complex technique with the use of anti-rat TSH or prolactin antibody. At 20 weeks, rats receiving MNU and ID diets had a 100% incidence of diffuse follicular goiter and multiple follicular adenomas of the thyroid. Focal proliferative thyroid follicular lesions including focal hyperplasias and adenomas per square centimeter of thyroid gland were significantly increased in rats given MNU and ID diets in comparison with rats given MNU and IA diets. At 33 weeks, all MNU rats on ID diets had a significantly increased incidence of thyroid carcinoma of the follicular or papillary types and diffuse pituitary thyrotroph hyperplasia, hypertrophy, and vacuolar degeneration. Rats fed ID diets without MNU had diffuse follicular goiter but no tumors at any time period. MNU given alone in rats fed IA diets induced a 10% incidence of single thyroid adenomas at 20 weeks and 70% at 33 weeks and a 10% incidence of thyroid carcinoma at 33 weeks. Tumors induced in other organs by MNU were not affected by the ID diets. Thus this experiment provided evidence that ID diets are potent promoters of thyroid tumors in this system, but the ID diet itself without carcinogen was not carcinogenic under the conditions of the study.

Animals↗
PubMed1984

Quantitative electron microscopic analysis of changes in peroxisomes and endoplasmic reticulum induced in mice during hepatocarcinogenesis by diethylnitrosamine promoted by di(2-ethylhexyl)phthalate or phenobarbital.

Histochemical studies have shown that basophilic adenomas and carcinomas develop from basophilic foci in mice initiated with N-nitrosodiethylamine (DEN) and promoted by di(2-ethylhexyl)phthalate (DEHP), whereas eosinophilic liver tumors promoted by phenobarbital (PhB) arose from eosinophilic foci. In this experiment, the ultrastructure of tumorous and nontumorous areas of the liver from these two groups of mice was analyzed by quantitative morphometric methods. It is shown that nontumorous liver in DEN- and DEHP-treated mice demonstrate a pronounced proliferation of peroxisomes that is also present in liver tumors induced by DEHP alone but not in liver tumors after DEN initiation and DEHP promotion. Initiation with DEN and promotion with PhB resulted in pronounced proliferation of smooth endoplasmic reticulum (ER) in both tumorous and nontumorous liver, whereas the number of peroxisomes remained unchanged.

Animals↗
PubMed1984

Transplantability of naturally occurring benign and malignant neoplasms and age-associated nonneoplastic lesions of the aging F344 rat as biological evidence for the histological diagnosis of neoplasms.

Portions of 162 naturally occurring neoplasms and 26 nonneoplastic lesions from 93 aged male or female F344/NCr rats were implanted into the left inguinal mammary fat pads of weanling syngeneic recipients. As controls, 95 normal tissues were implanted to the right inguinal fat pad. Transplant recipients were maintained for up to 1 year. Essentially, all types of naturally occurring benign and malignant tumors were successfully transplanted, i.e., grew progressively forming nodules and masses. For the transplants, the latency period preceding palpable growth, tumor growth rate, invasiveness, metastatic rate, and time to death were associated with the degree of histological malignancy of the primary tumor. The tumors which were the most malignant based on these criteria included large granular lymphocyte leukemia, sarcomas, and carcinomas. Fibromas, mammary fibroadenomas, and papillomas were easily transplanted but were not invasive. Endocrine tumors generally were the slowest-growing tumors. This study provides evidence that successful tumor transplantation is only evidence of neoplasia and does not distinguish whether a primary tumor is benign or malignant.

Aging↗
PubMed1983

Polypeptide transforming growth factors isolated from bovine sources and used for wound healing in vivo.

Transforming growth factors, which are polypeptides that induce the transformed phenotype in nonneoplastic cells, have been isolated in bulk amounts from bovine salivary gland and kidney. In experiments in which wound healing chambers were implanted subcutaneously in the backs of rats, these bovine transforming growth factors accelerated the accumulation of total protein, collagen, and DNA in treated chambers. These studies thus show an effect of an isolated transforming growth factor in vivo.

Animals↗