Biomedical subjects

L C Stephens

Publications and source records attributed to L C Stephens.

At least 127 records · Page 7Linked to original sources

PubMed1991

Apoptosis in irradiated murine tumors.

Early radiation responses of transplantable murine ovarian (OCaI) and hepatocellular (HCaI) carcinomas were examined at 6, 24, 48, 96, and 144 h after single photon doses of 25, 35, or 45 Gy. Previous studies using tumor growth delay and tumor radiocurability assays had shown OCaI tumors to be relatively radiosensitive and HCaI tumors to be radioresistant. At 6 h, approximately 20% of nuclei in OCaI tumors showed aberrations characteristic of cell death by apoptosis. This contrasted to an incidence of 3% in HCaI tumors. Mitotic activity was eliminated in OCaI tumors but was only transiently suppressed in HCaI tumors. At 24-96 h, OCaI tumors continued to display apoptosis and progressive necrosis, whereas HCaI tumors responded by exhibiting marked pleomorphism. Factors other than mitotic activity may influence tumor radiosensitivity, and one of these may be susceptibility to induction of apoptosis (programmed cell death), because this was a prominent early radiation response by the radiosensitive OCaI tumors.

Animals↗

PubMed1990

Early events in the import/assembly pathway of an integral thylakoid protein.

The light-harvesting chlorophyll a/b protein (LHCP) is nuclear-encoded and must traverse the chloroplast envelope before becoming integrally assembled into thylakoid membranes. Previous studies implicated a soluble stromal form of LHCP in the assembly pathway, but relied upon assays in which the thylakoid insertion step was intentionally impaired [Cline, K., Fulsom, D. R. and Viitanen, P. V. (1989) J. Biol. Chem. 264, 14225-14232]. Here we have developed a rapid-stopping procedure, based upon the use of HgCl2, to analyze early events of the uninhibited assembly process. With this approach, we have found that proper assembly of LHCP into thylakoids lags considerably behind trans-envelope translocation. During the first few minutes of import, two distinct populations of mature-size LHCP accumulate within the chloroplast. One is the aforementioned soluble stromal intermediate, while the other is a partially (or improperly) assembled thylakoid species. Consistent with precursor/product relationships, both species reach peak levels at a time when virtually none of the imported molecules are correctly assembled. These results confirm and extend our previous interpretation, that upon import, preLHCP is rapidly processed to its mature form, giving rise to a soluble stromal intermediate. They further suggest that the stromal intermediate initially inserts into the thylakoid bilayer in a partially assembled form, which eventually becomes properly assembled into the light-harvesting complex.

Biological Transport↗

PubMed1990

Inhibition of the promotional phase of azoxymethane-induced colon carcinogenesis in the F344 rat by calcium lactate: effect of simulating two human nutrient density levels.

The effects of 2 levels of dietary calcium and 2 types of dietary fat on the promotional phase phase of azoxymethane-induced colon cancer in the F344 rat were investigated. During the initiation phase of carcinogenesis all animals were fed a 5% corn oil AIN-76A diet containing 0.32% Ca in the form of calcium lactate. Rats were then injected with azoxymethane (AOM) weekly for 8 weeks. Thereafter, the rats were fed 1 of 3 diet formulations: a 5% corn oil diet or a 20% corn oil or 20% American Blend oil fat diet, with the level of Ca set at either 0.32% of the diet, a nutrient density simulating a daily human intake of approximately 1700 mg Ca/day, or at 0.04% of the diet, reflecting a human daily intake of approximately 200-250 mg of Ca/day, thus modeling 2 human nutrient density levels for calcium. Measurements of fecal pH during the experiment indicated an acidic adaptation of the large bowel to the lactate anion. Analysis of collected fecal samples showed more total fatty acids to be present in the colon when higher amounts of calcium were consumed. However, results of the tumorigenesis study indicated that calcium lactate fed at the 0.32% level significantly inhibited the development of colonic adenocarcinoma in all dietary groups. Taken together, this investigation supports the hypothesis that calcium supplementation can inhibit colon neoplasia in rats fed a high fat diet; however, under the conditions of this study, the 20% fat level did not significantly promote colon cancer as compared to a 5% fat level.

Animals↗

PubMed1990

Radiation myelopathy in primates treated with conventional fractionation.

A rhesus monkey model was used to assay the radiation tolerance of the spinal cord to 60Co radiation given in 2.2 Gy fractions. The D50 was found to be 76.1 Gy (SEM = 1.9 Gy); the estimated doses for 1% and 0.1% myelopathy were 59.1 +/- 5.5 Gy and 52.1 +/- 7.1 Gy, respectively. The latent period ranged from 5 to 20 months and decreased with increasing dose. All symptomatic animals had white-matter parenchymal lesions involving major motor tracts, and most also had vascular lesions in the white matter. Spinal cords of asymptomatic animals had either no histopathologic changes or small white-matter lesions that did not involve motor tracts.

Animals↗

PubMed1990

Adjuvant therapy for intracoronary stents. Investigations in atherosclerotic swine.

Early thrombosis has complicated human stent implantation in several trials. To determine the best anticoagulation/antiplatelet therapy to maintain stent patency after percutaneous transluminal coronary angioplasty, we implanted the flexible balloon-expandable coil stent into the left anterior descending coronary artery of 28 atherosclerotic 8-month-old Hanford miniature swine. Animals were randomly assigned to one of three treatment groups: group A, aspirin (1 mg/kg/day) and dipyridamole (1 mg/kg three times a day); group B, aspirin and dipyridamole (same doses) plus Coumadin (dose required to prolong prothrombin time 1.3-1.5-fold that of normal); and group C, control. Adjuvant therapy was begun 3 days before stenting. Two pigs (one from group A and one from group B) died during implantation, both without thrombosis. Twenty-six animals survived until follow-up angiography and sacrifice at 1 month. No occlusive thrombosis of the stent occurred in survivors. Reduction of the stent lumen diameter was observed in every case at follow-up. Percent lumen reduction was 19% in group A, 26% in group B, and 24% in group C. Marked smooth muscle cell hyperplasia was seen by light and transmission electron microscopy at stent struts. Scanning electron microscopy of the luminal surface showed a variable morphology consisting of normal endothelium, adherent leukocytes, stellate periluminal cells, and occasional fibrin strands and red blood cells. Luminal narrowing was not affected by anticoagulation therapy, antiplatelet drugs, cholesterol level, or stent sizing. We conclude that occlusive thrombosis does not complicate stent implantation in this model but that substantial luminal narrowing due in part to smooth muscle hyperplasia does occur. The significance of luminal narrowing at the stent site requires further study.

Angiography↗

PubMed1990

Modified methodology to improve flow cytometric DNA histograms from paraffin-embedded material.

Flow Cytometric (FCM) DNA content analysis of paraffin-embedded tissues has become a widely accepted procedure in assessing the biologic course in some tumors from archival material. Difficulty in interpreting histograms is frequently due to high levels of debris, and wide coefficients of variation (CV). These may lead to underestimating near-diploid abnormality. Although the clinical significance of low-degree aneuploidy has yet to be established, the procedure reported here improved our endeavor to detect DNA Indices (DI) of at least 1.1%. Experience has shown that careful technique can result in overall improvement of DNA histograms by lowering levels of debris and % CV, dramatically so in some cases. Archival histograms can be generated that rival in quality fresh tissue results. Archival material is currently employed for diagnostic and research purposes.

DNA, Neoplasm↗

PubMed1989

Preclinical toxicity and pharmacology of liposome-entrapped cis-bis-neodecanoato-trans-R,R-1,2-diaminocyclohexane platinum(II).

Liposome-entrapped cis-bis-neodecanoate-trans-R,R-1,2-diaminocylohexane platinum(II) (L-NDDP) is a new lipophilic cisplatin derivative formulated in a liposomal carrier currently in phase I clinical trials. The preclinical toxicity and pharmacology of L-NDDP were studied in mice and dogs. At the LD50 dose (i.v. bolus) in mice (60.5 mg/kg or 181.5 mg/m2), a tenfold decrease in the granulocyte and platelet counts was observed in the absence of renal toxic effects. In dogs, the maximum tolerated dose (MTD) of L-NDDP given i.v. over a period of 45-60 min was 150 mg/m2. This dose produced significant vomiting (6-18 episodes), minimal renal dysfunction, a maximal decrease in granulocyte and platelet counts of from 30% to 70%, and acute and transient elevation of liver enzymes. Higher doses (225 and 300 mg/m2) resulted in severe gastrointestinal (GI) toxicity in one animal and the death of two others within 48 h. Autopsy results showed multifocal hemorrhages in the lungs, GI tract, kidney, and liver. Three dogs were treated monthly with the MTD up to a cumulative dose of 637.5-712.5 mg/m2 with excellent tolerance. No cumulative myelosuppression or liver dysfunction was observed, whereas a slight increase in the creatinine baseline level was detected in all three animals. Autopsy results at the end of the study showed mild changes limited to the liver, kidney, and GI tract. Pharmacologic studies showed that the drug was cleared, fitting a two-compartment model with a mean t1/2 alpha of 7.1 min and a t1/2 beta of 87.8 h. These studies show that L-NDDP can safely be given at therapeutic doses to animals and that the dose-limiting toxic effects consists of myelosuppression in mice and a multiorgan hemorrhagic syndrome related to vascular injury in dogs.

Animals↗

PubMed1989

Daunorubicin-induced mammary tumors in the rat.

Eleven of 24 female Sprague-Dawley rats given a single i.v. injection of daunorubicin (10 mg/kg) developed mammary tumors within 8 months after the injection. Four of 12 rats given an intramammary injection of daunorubicin (4 or 8 micrograms) developed five mammary tumors in the injected area within 6.5 months of injection. Tissue distribution studies using tritiated daunorubicin revealed that the liver, kidney, lung, heart, and intestine had higher daunorubicin concentrations than mammary tissue during the first 24 h after i.v. injection. However, depletion of the drug from the internal organs was more rapid than from mammary tissue. Differences in ability to metabolize daunorubicin were compared in homogenates of isolated mammary epithelial cells and hepatocytes by high-performance liquid chromatography: after 90 min, hepatocytes metabolized about 70% of daunorubicin, whereas mammary epithelial cells did not metabolize the drug. Tritiated daunorubicin injected directly into rat mammary gland showed no metabolism in 24 h, and the drug did not get into the circulation. These results suggest that retention of daunorubicin because of the inability of mammary tissue to metabolize the drug is a cause of drug-induced mammary tumors in female Sprague-Dawley rats.

Adenocarcinoma↗

PubMed1989

The role of ultraviolet radiation in the induction of melanocytic skin tumors in inbred mice.

The purpose of these studies was to determine whether ultraviolet radiation contributes to the induction of cutaneous melanocytic tumors in mice. At 4 days of age, C3H/HeNCr(MTV-) mice received an initiating dose of 7,12-dimethylbenz(a)anthracene, followed by twice weekly applications of croton oil. Of the mice treated with this protocol, 31% developed melanoma. The addition of chronic doses of ultraviolet radiation (UVR) to the carcinogen treated site dramatically accelerated the development of the melanomas. Substituting UVR for the initiator or the promoter in this two-stage carcinogenesis model resulted in the development of a few melanocytic tumors (less than 10%). These experiments demonstrate that UVR accelerated the development of cutaneous melanocytic tumors induced in mice by chemical carcinogens and participated in the induction of these tumors by serving as a weak initiator or promoter.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed1989

Glands of the eyelids of rhesus monkeys (Macaca mulatta).

The various glands of rhesus monkey eyelids and human eyelids are similar. Numerous modified sebaceous glands are located along the tarsus. These conform with the meibomian glands, while typical sebaceous glands associated with the hair follicles of the lashes are consistent with the glands of Zeis. Lobules of accessory lacrimal tissue, corresponding to the glands of Krause and Wolfring, are located in the conjunctiva of the fornix and along the orbital border of the tarsal plate. Goblet cells are plentiful in the mucosa of the palpebral and bulbar conjunctiva, and along the lid margin are the sweat glands of Moll.

Animals↗

PubMed1989

Response of parotid gland organ culture to radiation.

Organ cultures of rhesus parotid tissue in medium enriched with homologous serum and supplemented with low levels of isoproterenol were irradiated with single photon doses of 2.5, 5.0, 7.5, 10.0, 12.5, or 15.0 Gy. Following irradiation, the tissue was incubated while being agitated for 24 h; then it was fixed in formalin. Microscopically, death of serous acinar cells was seen in areas unaltered by autolysis. Based on the numbers of nuclear aberrations, the dose response did not differ significantly from that observed at 24 h in parotid gland irradiated in vivo. The similar rapid response under the two conditions shows that apoptosis of irradiated parotid serous cells is a direct expression of interphase cell death.

Animals↗

PubMed1988

Chemoprevention of N-nitrosomethylbenzylamine-induced esophageal cancer in rats by the naturally occurring thioether, diallyl sulfide.

Diallyl sulfide (DAS) is a principal thioether of garlic (Allium sativum) accounting, in part, for the flavor and fragrance of this herb. Previous studies have shown that DAS is a potent inhibitor of experimentally induced colon cancer in mice. Metabolic studies of other garlic-derived substances suggested that DAS could prevent tumorigenicity of other hepatic activated carcinogens. The present study was designed to determine whether DAS could inhibit the DNA-damaging and tumorigenic effects of N-nitrosomethylbenzylamine in rat esophagus. A dose of 200 mg/kg of DAS given p.o. 3 h prior to N-nitrosomethylbenzylamine administration was found to inhibit the carcinogen-induced nuclear toxicity by 64% to 56% at the two doses (3 and 5 mg/kg) of NMBA tested. These results suggested that the compound was potentially anticarcinogenic. In the carcinogenicity experiment it was found that DAS totally inhibited tumor formation in rats treated with a carcinogenic dose of NMBA (100% inhibition of papilloma and squamous cell carcinoma incidence, P less than 0.0001). Additionally DAS was found to substantially reduce hepatic microsomal metabolism of the carcinogen. These data demonstrate that DAS is unique in its anticarcinogenic activity. It strongly suppresses the tumorigenic effects of potent, metabolically activated monoalkylating carcinogens in the gastrointestinal tract.

Allyl Compounds↗

PubMed1988

Effect of cis-diamminedichloroplatinum(II) combined with whole body hyperthermia on renal injury.

The effect of whole body hyperthermia (WBH) on cis-diamminedichloroplatinum (II) (DDP) induced renal toxicity and antitumor effect was studied using a F344 rat model. Renal injury at 5 and 14 days after treatment was evaluated using animal mortality, renal functional assays (blood urea nitrogen, creatinine), and histopathological methods. WBH (120 min at 41.5 degrees C) enhanced both antitumor effects and toxic side effects. The latter included increased mortality, increased blood urea nitrogen and creatinine levels, and increased renal damage. After simultaneous treatment with WBH and DDP, thermal enhancement ratios (TER) for renal damage between 2.5 and 3.0 were calculated. The histopathological changes observed in the kidney after DDP alone or combined with WBH were primarily found in the proximal pars recta tubules (S3 segment) in the outer stripe of the outer medulla. There was no qualitative difference in tubular damage between rats treated with DDP alone or those treated with DDP combined with WBH. However, at a fixed DDP dose, damage in the combined treatment modality group was significantly greater than in the DDP-only treated group.

Animals↗

PubMed1988

Acute radiation injury of ocular adnexa.

Eyelids and lacrimal glands of monkeys examined histologically 24 and 48 hours after receiving 2.5 to 20.0 Gy (250 to 2000 rad) of cobalt 60 radiation contained acute inflammation. Cells of meibomian glands, other sebaceous glands, sweat glands, and goblet cells displayed no significant alterations. Acinar cells of major and accessory lacrimal glands and, to a lesser degree, lacrimal duct epithelium showed degeneration and necrosis that were increased in extent in proportion to the radiation dose. Reduced numbers of serous acini and decreased size of remaining acini indicate that atrophy of lacrimal glands can be recognized within two days after irradiation. The morphologic diagnosis for irradiated lacrimal glands was acute, necrotizing dacryoadenitis.

Acute Disease↗

PubMed1988

Analysis of the histopathology of radiation myelopathy.

An analysis of published histopathology reports of patients with radiation myelopathy was performed. Radiation lesions in the spinal cord were classified as primarily white matter parenchymal lesions (type 1), primarily vascular lesions (type 2), or a combination of vascular and white matter lesions (type 3). The presence or absence of a mononuclear inflammatory reaction was also noted. Type 1 and type 3 lesions had comparable latent periods, both significantly shorter than those observed for type 2 lesions. The anatomical level of the irradiation did not appear to influence the type of lesion. Inflammatory reaction was observed with greater frequency in type 3 lesions. For all types of lesions, the average latent periods in patients with inflammatory reactions were shorter than in those without inflammation. In the cases in which disease status was evaluated, 70% of the patients were free of disease or had no evidence of recurrence at autopsy.

Humans↗

PubMed1987

Enhanced cardiotoxicity in rabbits treated with verapamil and adriamycin.

Verapamil, a calcium channel blocker, reduces resistance of some tumors to Adriamycin by inhibiting Adriamycin efflux from resistant cells. This study shows that rabbits given 7 mg/kg of Adriamycin and 0.8 mg/kg of verapamil died earlier with functional and morphological cardiac abnormalities than rabbits given Adriamycin alone. Rabbits that were given verapamil and died peracutely had higher concentrations of Adriamycin in the myocardium. The relatively high dose of Adriamycin was expected to produce cardiotoxicity in rabbits within a matter of days. However, peracute death (within hours) in rabbits given the same dose of Adriamycin but with verapamil treatment was unexpected. These results suggest that combining Adriamycin with verapamil increases early cardiac toxicity. Therefore, clinical use of this combination should be approached cautiously until the interactions, including the possibility for enhanced normal tissue damage, are fully understood.

Animals↗

PubMed1987

Experimental combination chemotherapy: intracarotid versus intravenous administration of aziridinylbenzoquinone, BCNU, and cisplatin in dogs.

Sixteen adult beagles (10-12 kg) were used to evaluate combinations of 2,5-diaziridinyl-3,6-biscarboethoxyamino-1,4-benzoquinone (AZQ, aziridinylbenzoquinone), 1,3-bis-2-chloroethyl-1-nitrosourea (BCNU, carmustine), and cis-dichlorodiammineplatinum(II) (CDDP, cisplatin) administered by intravenous or intracarotid infusion. Moderate to severe systemic toxicities resulted from all drug infusions, but no histopathologic changes were found in the central nervous system (CNS) of any of the dogs. Results indicated that the toxicities were not dependent on the route of administration or the recipient's gender, and they were reversible in most cases with intravenous supportive therapy. Cisplatin seemed to have an additive effect when administered in combination with AZQ and/or BCNU.

Animals↗

PubMed1987

Anatomy of the major lacrimal gland of rhesus monkeys (Macaca mulatta).

The major lacrimal gland of rhesus monkeys is impalpable within the fatty connective tissue of the upper lateral quadrant of the orbit. Acini of the lacrimal glands are composed of both sparsely and heavily granulated cells that histochemically resemble serous acinar cells of the submandibular salivary gland. The cytoplasmic granules are strongly periodic acid-Schiff (PAS)-positive, and some are also stained by alcian blue for acidic mucosubstances. The lacrimal gland has a simple duct system of intralobular ducts and interlobular excretory ducts. Lymphocytes and plasma cells are common in the periductal stroma. Major lacrimal glands of rhesus monkeys are suitable for comparative and correlative studies of lacrimal and salivary diseases and radiation responses.

Animals↗