39 results on '"Carol J. Detrisac"'
Search Results
2. Data from Increased Levels of the FoxM1 Transcription Factor Accelerate Development and Progression of Prostate Carcinomas in both TRAMP and LADY Transgenic Mice
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Robert H. Costa, Alexander Lyubimov, Vladimir V. Kalinichenko, Carol J. Detrisac, Michael L. Major, Timothy J. Ackerson, I-Ching Wang, and Tanya V. Kalin
- Abstract
The proliferation-specific Forkhead Box M1 (FoxM1 or FoxM1b) transcription factor is overexpressed in a number of aggressive human carcinomas. Mouse hepatocytes deficient in FoxM1 fail to proliferate and are highly resistant to developing carcinogen-induced liver tumors. We previously developed a transgenic (TG) mouse line in which the ubiquitous Rosa26 promoter was used to drive expression of the human FoxM1b cDNA transgene in all mouse cell types. To investigate the role of FoxM1b in prostate cancer progression, we bred Rosa26-FoxM1b mice with both TRAMP and LADY TG mouse models of prostate cancer. We show that increased expression of FoxM1b accelerated development, proliferation, and growth of prostatic tumors in both TRAMP and LADY double TG mice. Furthermore, development of prostate carcinomas in TRAMP/Rosa26-FoxM1b double TG mice required high levels of FoxM1 protein to overcome sustained expression of the alternative reading frame tumor suppressor, a potent inhibitor of FoxM1 transcriptional activity. Depletion of FoxM1 levels in prostate cancer cell lines PC-3, LNCaP, or DU-145 by small interfering RNA transfection caused significant reduction in proliferation and anchorage-independent growth on soft agar. This phenotype was associated with increased nuclear levels of the cyclin-dependent kinase inhibitor protein p27Kip1 and diminished expression of S-phase promoting cyclin A2 and M-phase promoting cyclin B1 proteins. Finally, we show that elevated levels of FoxM1 protein correlate with high proliferation rates in human prostate adenocarcinomas. Our results suggest that the FoxM1 transcription factor regulates development and proliferation of prostate tumors, and that FoxM1 is a novel target for prostate cancer treatment. Cancer Res 2006; 66(3): 1712-20
- Published
- 2023
3. Oral toxicity and pharmacokinetic studies of SHetA2, a new chemopreventive agent, in rats and dogs
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Alexander Zakharov, Dejan Nikolic, Aryamitra Banerjee, Tomas Martin-Jimenez, Irina Mankovskaya, Lian Chen, Alexander V. Lyubimov, Izet M. Kapetanovic, Emmanuel Onua, Richard B. van Breemen, Doris M. Benbrook, Nancy Dinger, Marcia Pereira, Kasim K. Kabirov, and Carol J. Detrisac
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Male ,No-observed-adverse-effect level ,Health, Toxicology and Mutagenesis ,Metabolite ,Retinoic acid ,Administration, Oral ,Motor Activity ,Pharmacology ,Weight Gain ,Toxicology ,Rats, Sprague-Dawley ,Eating ,chemistry.chemical_compound ,Dogs ,Species Specificity ,Pharmacokinetics ,Adrenal Glands ,Toxicity Tests ,Animals ,Anticarcinogenic Agents ,Medicine ,Chromans ,No-Observed-Adverse-Effect Level ,Chemical Health and Safety ,business.industry ,Prostate ,Public Health, Environmental and Occupational Health ,Thiones ,Organ Size ,General Medicine ,Rats ,Bioavailability ,Lowest-observed-adverse-effect level ,chemistry ,Apoptosis ,Area Under Curve ,Toxicity ,Female ,business - Abstract
SHetA2 is a heteroarotinoid that has shown selective inhibition of cancer cell growth and an induction of apoptosis without activation of nuclear retinoic acid receptors. In the rat study, SHetA2 was administered in 1% aqueous methylcellulose/0.2% Tween 80 by oral gavage at 0, 100, 500, and 2,000 mg/kg/day for 28 days. The high-dose administration induced decreased activity in male rats, decreased body-weight gains and food consumption, and changes in organ weights. The major metabolite of SHetA2 in rat plasma was monohydroxy SHetA2, which was considerably higher than the parent compound after oral and intravenous administration. Pharmacokinetic analysis showed extremely low (1%) systemic bioavailability of SHetA2 for all doses tested. The dose of 2,000 mg/kg/day was considered as the lowest observed adverse effect level. The no observed adverse effect level (NOAEL) was 500 mg/kg/day. In the dog study, no toxicity of SHetA2 in 30% aqueous Solutol(®) HS 15 was observed in any tested dose groups (0, 100, 400, and 1,500 mg/kg/day). The major metabolite of SHetA2 in dog plasma was also monohydroxy SHetA2, which was equal to or lower than the parent compound after oral administration. SHetA2 levels in dog plasma were notably higher, when compared to levels in rat plasma. However, exposure was not dose proportional, as exemplified by a lack of proportional increase in maximum concentration or area under the plasma concentration-time curve with increasing dose. The NOAEL was not established and was considered to be above 1,500 mg/kg/day.
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- 2012
4. Establishment of a Swiss Webster Mouse Model of Pneumonic Plague To Meet Essential Data Elements under the Animal Rule
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Narayanan Rajendran, Louis Holland, Jessica Price, Winston Lin, Mark Bolanowski, Carol J. Detrisac, Bruce Gingras, Shu-Chieh Hu, Robert V. House, and P.F. Fellows
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Male ,Microbiology (medical) ,Pneumonic plague ,medicine.medical_specialty ,Yersinia pestis ,Clinical Biochemistry ,Immunology ,Bubonic plague ,Median lethal dose ,Lethal Dose 50 ,Mice ,medicine ,Animals ,Humans ,Immunology and Allergy ,Plague ,Plague Vaccine ,Vaccines ,Clinical pathology ,biology ,Lethal dose ,Animal Structures ,medicine.disease ,biology.organism_classification ,Disease Models, Animal ,Plague vaccine ,Female ,Pneumonia (non-human) - Abstract
A recombinant vaccine (rF1V) is being developed for protection against pneumonic plague. This study was performed to address essential data elements to establish a well-characterized Swiss Webster mouse model for licensing the rF1V vaccine using the FDA's Animal Rule. These elements include the documentation of challenge material characteristics, aerosol exposure parameters, details of the onset and severity of clinical signs, pathophysiological response to disease, and relevance to human disease. Prior to animal exposures, an evaluation of the aerosol system was performed to determine and understand the variability of the aerosol exposure system. Standardized procedures for the preparation ofYersinia pestischallenge material also were developed. The 50% lethal dose (LD50) was estimated to be 1,966 CFU using Probit analysis. Following the LD50determination, pathology was evaluated by exposing mice to a target LD99(42,890 CFU). Mice were euthanized at 12, 24, 36, 48, 60, and 72 h postexposure. At each time point, samples were collected for clinical pathology, detection of bacteria in blood and tissues, and pathology evaluations. A general increase in incidence and severity of microscopic findings was observed in the lung, lymph nodes, spleen, and liver from 36 to 72 h postchallenge. Similarly, the incidence and severity of pneumonia increased throughout the study; however, some mice died in the absence of pneumonia, suggesting that disease progression does not require the development of pneumonia. Disease pathology in the Swiss Webster mouse is similar to that observed in humans, demonstrating the utility of this pneumonic plague model that can be used by researchers investigating plague countermeasures.
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- 2012
5. Subchronic oral toxicity and metabolite profiling of the p53 stabilizing agent, CP-31398, in rats and dogs
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David L. McCormick, Miguel Muzzio, Izet M. Kapetanovic, Carol J. Detrisac, Levy Kopelovich, and William D. Johnson
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Male ,Protein Conformation ,Administration, Oral ,Ovary ,Pharmacology ,Biology ,Kidney ,Toxicology ,Beagle ,Article ,Excipients ,Dogs ,In vivo ,Oral administration ,medicine ,Animals ,Dose-Response Relationship, Drug ,Protein Stability ,Kidney metabolism ,Rats ,Dose–response relationship ,Pyrimidines ,medicine.anatomical_structure ,Toxicity ,Metabolome ,Female ,Tumor Suppressor Protein p53 - Abstract
CP-31398 (N'-[2-[2-(4-methoxyphenyl)ethenyl]-4-quinazolinyl]-N,N-dimethyl-1,3-propanediamine dihydrochloride) is a styrylquinazoline that stabilizes the DNA binding conformation of p53, thereby maintaining the activity of p53 as a transcription factor and tumor suppressor. In consideration of the potential use of p53 stabilizers for cancer prevention and therapy, 28-day studies (with recovery) were performed to characterize the toxicity of CP-31398 in rats and dogs. In the rat study, groups of 15 CD rats/sex received daily gavage exposure to CP-31398 at 0, 40, 80, or 160mg/kg/day (0, 240, 480, or 960mg/m(2)/day). In the dog study, groups of five beagle dogs received daily gavage exposure to CP-31398 at 0, 10, 20, or 40mg/kg/day (0, 200, 400, or 800mg/m(2)/day). The high dose of CP-31398 induced mortality in both species: seven male rats and four female rats died as a result of hepatic infarcts, and two female dogs died as a result of hepatic necrosis without evidence of thrombosis. No deaths were seen in the mid- or low-dose groups in either species. In dogs, sporadic emesis was seen in the high dose and mid dose groups, and reductions in body weight gain were observed in all drug-exposed groups. CP-31398 induced mild anemia in both species; clinical pathology data also demonstrated hepatic toxicity, renal toxicity, inflammatory reactions, and coagulopathies in rats in the high dose and mid dose groups. Treatment-related microscopic changes in high dose and mid dose rats were identified in the liver, kidney, heart, bone marrow, lung, adrenals, spleen, thymus, skeletal muscle, and ovary; microscopic changes in the liver, heart, lung, and adrenals persisted through the recovery period. In dogs, microscopic changes were identified in the central nervous system, lung, and liver; changes in all tissues remained at the end of the recovery period. The liver is the primary site of limiting toxicity for CP-31398 in rats, and is also a key site of toxicity in dogs. The maximum tolerated dose (MTD) for subchronic oral administration of CP-31398 is 80mg/kg/day (480mg/m(2)/day) in rats and 20mg/kg/day (400mg/m(2)/day) in dogs. Although only modest and apparently reversible toxicities (microscopic changes in rats; reductions in body weight gain and alterations in red cell parameters in dogs) were seen in the low dose groups, no observed adverse effect levels (NOAELs) for CP-31398 could not be established for either species. The toxicity of CP-31398 suggests that this agent may not be suitable for use in cancer prevention. However, should in vivo antitumor efficacy be achievable at doses that do not induce limiting toxicity, CP-31398 may have utility as a cancer therapeutic. Modification of the primary sites of CP-31398 metabolism (N-demethylation of the alkyl side chain; hydroxylation and O-demethylation of the styryl benzene group) may result in the development of CP-31398 analogs with comparable pharmacologic activity and reduced toxicity.
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- 2011
6. Progress in Biological Threat Agent Vaccine Development
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Leonard A. Smith, Daniel E. McLain, Changhong Y. Lindsey, Thomas L. Horn, and Carol J. Detrisac
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Male ,Biological Products ,No-Observed-Adverse-Effect Level ,Vaccines, Synthetic ,REPEAT DOSE TOXICITY ,Dose-Response Relationship, Immunologic ,Drug Evaluation, Preclinical ,Biological Warfare Agents ,Ricin ,Biology ,Toxicology ,Antibodies, Neutralizing ,Virology ,law.invention ,Ricin toxin ,law ,Immunoglobulin G ,Models, Animal ,Toxicity ,Escherichia coli ,Recombinant DNA ,Animals ,Female ,Rabbits ,New zealand white - Abstract
A recombinant ricin toxin A-chain 1-33/44-198 vaccine (RV Ec) was administered to male and female New Zealand white (NZW) rabbits (10/sex/group) in a repeat-dose toxicity study. The RV Ec vaccine was administered on study days 1, 29, 57, and 85 via intramuscular (IM) injection (0, 100, or 200 μg/dose). All study animals were observed throughout treatment until euthanized and submitted for necropsy on study day 88 or 99 (recovery period). There were no treatment-related or toxicologically significant effects observed. There were no statistically significant differences noted in the antibody titers and/or concentrations in 100 μg RV Ec-treated animals when compared to 200 μg RV Ec-treated animals, suggesting that both doses produced comparable antibody titers/concentrations during the study. The highest immune response was observed on study day 99 (ie, 2 weeks after the last dose). The immune response observed demonstrated that RV Ec is biologically active in the rabbit model, with no apparent marked sex differences.
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- 2011
7. Abstract 4933: Six-month oral toxicity study of endoxifen in rats
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Elizabeth R. Glaze, David L. McCormick, Patrick T. Curry, Thomas L. Horn, William D. Johnson, and Carol J. Detrisac
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Cancer Research ,medicine.medical_specialty ,Clinical pathology ,Uterus ,Physiology ,Ovary ,Hyperplasia ,medicine.disease ,Endometrial hyperplasia ,Gross examination ,medicine.anatomical_structure ,Oncology ,Oral administration ,Toxicity ,medicine - Abstract
The tamoxifen metabolite, endoxifen (N-desmethyl-4-hydroxytamoxifen), is being developed for oral and local topical administration for prevention and therapy of breast cancer. As part of this development, the toxicity of oral endoxifen was evaluated in a chronic (six-month) study in rats. Groups of 25 female CD rats received daily oral (gavage) exposure to endoxifen at doses of 0 (vehicle control), 5, or 50 mg/kg/day for six months. In vivo assessments included survival; clinical and physical signs of toxicity; body weight; food consumption; ophthalmology; and clinical pathology (clinical chemistry, hematology, coagulation). Fifteen rats per group were euthanized and necropsied after six months of endoxifen exposure; remaining rats in each group were euthanized and necropsied after a four-week recovery period. All gross lesions and approximately 45 tissues per animal were evaluated microscopically. In addition, bone marrow smears collected from rats euthanized for the six month necropsy were evaluated for DNA damage (micronucleus assessment). Daily oral administration of endoxifen at 5 or 50 mg/kg/day for six months induced no treatment-related mortality, clinical evidence of toxicity, or effects on ophthalmology. Endoxifen was not genotoxic, as it had no effect on the incidence of bone marrow micronuclei. Both dose levels of endoxifen induced similar suppressions of body weight gain; food consumption was also significantly decreased in both endoxifen-treated groups. Both dose levels of endoxifen induced gross and microscopic changes in hormone-sensitive tissues. Gross pathology was identified at necropsy in the ovary (cysts) and uterus (small) in both endoxifen groups; mean relative ovarian weight was increased and mean relative uterine weight was decreased in endoxifen groups. Microscopic findings were identified in the ovaries (corpora lutea depletion, cysts), uterus (atrophy, endometrial hyperplasia), cervix (mucinous hypertrophy), mammary gland (hyperplasia), and pituitary gland (vacuolation). These changes are consistent with the activity of endoxifen as an endocrine disruptor, and suggest effects on the hypothalamic-pituitary-gonadal axis. After six months of daily oral administration, both dose levels of endoxifen induced significant reductions in body weight gain and food consumption; alterations in the weights of hormone-sensitive organs; and gross and microscopic effects, primarily in hormone-sensitive tissues. Most of the effects of endoxifen observed in this study can be ascribed to its potent antiestrogenic activity, and are interpreted as signs of its pharmacologic action. However, the gross and microscopic changes seen at both dose levels of endoxifen used in this study demonstrate that a No Observed (Adverse) Effect Level (NO[A]EL) for daily oral administration of endoxifen to female rats for six months could not be determined. [Supported by HHSN261201500024I from the NCI, DHHS.] Citation Format: Thomas L. Horn, William D. Johnson, Carol J. Detrisac, Patrick T. Curry, Elizabeth R. Glaze, David L. McCormick. Six-month oral toxicity study of endoxifen in rats [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4933.
- Published
- 2018
8. Assessment of oral toxicity and safety of pentamethylchromanol (PMCol), a potential chemopreventative agent, in rats and dogs
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Izet M. Kapetanovic, Matthew Lindeblad, Alexander V. Lyubimov, Irina Mankovskaya, Nancy Dinger, Carol J. Detrisac, Kasim K. Kabirov, and Alexander Zakharov
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Male ,medicine.medical_specialty ,Anemia ,Administration, Oral ,Toxicology ,Article ,Nephrotoxicity ,Dogs ,Oral administration ,Internal medicine ,Toxicity Tests ,Animals ,Anticarcinogenic Agents ,Medicine ,Dosing ,Chromans ,Adverse effect ,Dose-Response Relationship, Drug ,business.industry ,Stomach ,Organ Size ,medicine.disease ,Rats ,Endocrinology ,medicine.anatomical_structure ,Toxicity ,Female ,Histopathology ,Drug Screening Assays, Antitumor ,business - Abstract
2,2,5,7,8-Pentamethyl-6-chromanol (PMCol) was administered by gavage in rats for 28 days at dose levels of 0, 100, 500, and 2000mg/kg/day. PMCol administration induced decreases in body weight gains and food consumption, hepatotoxicity (increased TBILI, ALB, ALT, TP; increased relative liver weights; increased T4 and TSH), nephrotoxicity (increased BUN and BUN/CREAT, histopathology lesions), effect on lipid metabolism (increased CHOL), anemia, increase in WBC counts (total and differential), coagulation (FBGN upward arrow and PT downward arrow) and hyperkeratosis of the nonglandular stomach in the 2000mg/kg/day dose group (in one or both sexes). In the 500mg/kg/day dose group, toxicity was seen to a lesser extent. In the 100mg/kg/day dose group, only increased CHOL (females) was observed. To assess the toxicity of PMCol in male dogs it was administered orally by capsule administration for 28 days at dose levels of 0, 50, 200 and 800mg/kg/day (four male dogs/dose group). PMCol treatment at 800mg/kg/day resulted in pronounced toxicity to the male dogs. Target organs of toxicity were liver and thymus. Treatment at 200mg/kg/day resulted in toxicity consistent with slight adverse effect on the liver only. The results of the safety pharmacology study indicate that doses of 0, 50, 200 and 800mg/kg administered orally did not have an effect on the QT interval, blood pressures and body temperatures following dosing over a 24-h recording period. Under the conditions of this study, the no-observed-adverse effect level (NOAEL) for daily oral administration of PMCol by gavage for 28 days to male rats was 100mg/kg/day and 50mg/kg in male dogs. In female rats, the NOAEL was not established due to statistically significant and biologically meaningful increases in CHOL level seen in the 100mg/kg/day dose group. The results of these studies indicated that administration of PMCol at higher dose levels resulted in severe toxicity in dogs and moderate toxicity in rats, however, administration at lower levels is considered to be less likely to result in toxicity following 28 days of exposure. Sex-related differences were seen in rats. Male rats appeared to have greater sensitivity to nephrotoxicity, while female animals had a greater incidence of hepatoxicity and changes in hematological parameters evaluated, especially at a dose of 500mg/kg/day, which correlated to the higher plasma drug levels in female rats. It appeared that dogs were generally more sensitive than rats to oral administration of PMCol. Further examination of the potential toxic effects of PMCol in longer term studies is required prior to understanding the full risks of PMCol administration as a chemopreventative agent.
- Published
- 2010
9. Murine Oncogenicity and Pharmacokinetics Studies of 9-cis-UAB30, an RXR Agonist, for Breast Cancer Chemoprevention
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Carol J. Detrisac, Michael J. Cwik, David L. McCormick, William D. Johnson, Izet M. Kapetanovic, and Thomas L. Horn
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Male ,medicine.medical_specialty ,Carcinogenicity Tests ,medicine.drug_class ,Retinoic acid ,Breast Neoplasms ,Naphthalenes ,Pharmacology ,Oncogenicity ,Retinoid X receptor ,Biology ,Toxicology ,Mice ,chemistry.chemical_compound ,Breast cancer ,Pharmacokinetics ,Internal medicine ,medicine ,Animals ,Retinoid ,Mice, Knockout ,Hematology ,Dose-Response Relationship, Drug ,medicine.disease ,Mice, Inbred C57BL ,Retinoid X Receptors ,Endocrinology ,chemistry ,Area Under Curve ,Toxicity ,Fatty Acids, Unsaturated ,Female ,Tumor Suppressor Protein p53 - Abstract
The synthetic retinoic acid analog, 9- cis-UAB30 [(2E,4E,6Z,8E)-8-(3′,4′-dihydro-1′(2′H)-naphthalen-1′-ylidene)-3,7-dimethyl-2,4,6-octatrienoic acid], is a specific ligand for the retinoid X receptor. Murine oncogenicity and pharmacokinetics studies were performed as part of the preclinical development of 9- cis-UAB30 for breast cancer chemoprevention. In the oncogenicity study, TSG-p53(+/-) (p53 knockout) mice (25 per sex per group) received daily gavage exposure to 9- cis-UAB30 doses of 0 (control), 30, 100, or 300 mg/kg/d for 6 months. Positive controls received p-cresidine (400 mg/kg/d) for 6 months. 9- cis-UAB30 had no biologically significant effects on survival, body weight, body weight gain, clinical signs, hematology, or clinical chemistry but induced dose-related hepatomegaly in both sexes and decreased thymus weights in high-dose females. Gross and microscopic pathology provided no evidence of 9- cis-UAB30 toxicity or oncogenicity; by contrast, p-cresidine induced urinary bladder neoplasms in more than 60% of male and female mice. It was concluded that 9- cis-UAB30 is not oncogenic in p53(+/-) mice. In the pharmacokinetics study, C57BL/6 mice received daily gavage exposure to 9- cis-UAB30 (100 or 300 mg/kg/d) for 1 or 7 days. Pharmacokinetic parameters were similar after 1 and 7 days of dosing. Dose-related peak plasma levels of 9- cis-UAB30 were seen between 0.25 and 3 hours; volume of distribution was comparable at both dose levels. Increases in area under the curve were less than proportional to dose and were associated with an increased rate of apparent clearance and decreased elimination half-life. These results suggest decreased absorption and/or possible induction of clearance mechanisms. Enzyme induction may underlie the hepatomegaly seen in mice treated with 9- cis-UAB30 for 6 months in the oncogenicity study.
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- 2010
10. Subchronic Toxicity and Toxicogenomic Evaluation of Tamoxifen Citrate + Bexarotene in Female Rats
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James A. Crowell, Jennifer M. Naylor, Carol J. Detrisac, Karen E. O. Torres, David L. McCormick, Michael J. Cwik, Izet M. Kapetanovic, Ronald A. Lubet, and Thomas L. Horn
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medicine.medical_specialty ,Tetrahydronaphthalenes ,Receptors, Retinoic Acid ,medicine.drug_class ,Pharmacology ,Biology ,Toxicology ,Toxicogenetics ,Rats, Sprague-Dawley ,Internal medicine ,medicine ,Animals ,PPAR alpha ,Retinoid ,skin and connective tissue diseases ,Oligonucleotide Array Sequence Analysis ,Bexarotene ,Dose-Response Relationship, Drug ,Reverse Transcriptase Polymerase Chain Reaction ,Gene Expression Profiling ,Lipid metabolism ,Antiestrogen ,Rats ,Tamoxifen ,Retinoid X Receptors ,Endocrinology ,Liver ,Estrogen ,Toxicity ,Tamoxifen Citrate ,Female ,Dimerization ,hormones, hormone substitutes, and hormone antagonists ,medicine.drug - Abstract
Tamoxifen (TAM) is a nonsteroidal antiestrogen that prevents estrogen receptor-positive breast cancer in rodents and humans. Bexarotene (BEX), a selective agonist for retinoid X receptors, inhibits mammary carcinogenesis in rodents. The present study was conducted to support the preclinical development of TAM (tamoxifen citrate) + BEX for use in breast cancer chemoprevention, and to investigate the influence of these agents on hepatic gene expression. Female CD rats (20 per group) received daily oral (gavage) exposure to TAM (0 or 60 microg/kg/day) and/or BEX (0, 5, 15, or 45 mg/kg/day) for a minimum of 90 days. BEX induced mild, dose-related anemia and dose-related increases in serum alkaline phosphatase, cholesterol, triglycerides, and calcium levels, and increased platelet counts. TAM had no biologically significant effect on any clinical pathology parameter and did not alter the effects of BEX on these endpoints. Microscopic alterations induced by BEX included epidermal hyperplasia, hyperkeratosis (stomach), and cytoplasmic clearing (liver). Microscopic changes in TAM-treated rats were limited to mucous cell hypertrophy in the cervix and vagina. The toxicity of administration of the combination of TAM + BEX can generally be predicted on the basis of the toxicity of each drug as a single agent. BEX induced dose-related alterations in the expression of several genes involved in steroid, drug, and/or fatty acid metabolism; TAM did not alter these effects of BEX. Differential expression of genes involved in drug and lipid metabolism may underlie the observed effects of BEX on cholesterol and triglyceride levels and its effects on liver histology.
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- 2007
11. Increased Levels of the FoxM1 Transcription Factor Accelerate Development and Progression of Prostate Carcinomas in both TRAMP and LADY Transgenic Mice
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Vladimir V. Kalinichenko, Carol J. Detrisac, Tanya V. Kalin, Michael L. Major, Timothy Ackerson, I-Ching Wang, Alexander V. Lyubimov, and Robert H. Costa
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Male ,Genetically modified mouse ,Cancer Research ,RNA, Untranslated ,Cyclin A ,Mice, Transgenic ,Cell Growth Processes ,Adenocarcinoma ,Cyclin B ,Biology ,Transfection ,Article ,Mice ,Prostate cancer ,CDC2 Protein Kinase ,LNCaP ,medicine ,Animals ,Humans ,RNA, Messenger ,Cyclin B1 ,RNA, Small Interfering ,Forkhead Box Protein M1 ,Prostatic Neoplasms ,Proteins ,Cancer ,Forkhead Transcription Factors ,medicine.disease ,Mice, Inbred C57BL ,Oncology ,Disease Progression ,Cancer research ,FOXM1 ,biology.protein ,Cyclin A2 ,Tramp - Abstract
The proliferation-specific Forkhead Box M1 (FoxM1 or FoxM1b) transcription factor is overexpressed in a number of aggressive human carcinomas. Mouse hepatocytes deficient in FoxM1 fail to proliferate and are highly resistant to developing carcinogen-induced liver tumors. We previously developed a transgenic (TG) mouse line in which the ubiquitous Rosa26 promoter was used to drive expression of the human FoxM1b cDNA transgene in all mouse cell types. To investigate the role of FoxM1b in prostate cancer progression, we bred Rosa26-FoxM1b mice with both TRAMP and LADY TG mouse models of prostate cancer. We show that increased expression of FoxM1b accelerated development, proliferation, and growth of prostatic tumors in both TRAMP and LADY double TG mice. Furthermore, development of prostate carcinomas in TRAMP/Rosa26-FoxM1b double TG mice required high levels of FoxM1 protein to overcome sustained expression of the alternative reading frame tumor suppressor, a potent inhibitor of FoxM1 transcriptional activity. Depletion of FoxM1 levels in prostate cancer cell lines PC-3, LNCaP, or DU-145 by small interfering RNA transfection caused significant reduction in proliferation and anchorage-independent growth on soft agar. This phenotype was associated with increased nuclear levels of the cyclin-dependent kinase inhibitor protein p27Kip1 and diminished expression of S-phase promoting cyclin A2 and M-phase promoting cyclin B1 proteins. Finally, we show that elevated levels of FoxM1 protein correlate with high proliferation rates in human prostate adenocarcinomas. Our results suggest that the FoxM1 transcription factor regulates development and proliferation of prostate tumors, and that FoxM1 is a novel target for prostate cancer treatment. Cancer Res 2006; 66(3): 1712-20
- Published
- 2006
12. IRON STORAGE DISEASE IN CAPTIVE EGYPTIAN FRUIT BATS (ROUSETTUS AEGYPTIACUS): RELATIONSHIP OF BLOOD IRON PARAMETERS TO HEPATIC IRON CONCENTRATIONS AND HEPATIC HISTOPATHOLOGY
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James F. X. Wellehan, Gary Stevens, Carol J. Detrisac, Jeffery O. Hall, Lisa L. Farina, Darryl J. Heard, and Dana LeBlanc
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Male ,Pathology ,medicine.medical_specialty ,Iron ,Population ,Physiology ,Diagnosis, Differential ,Fibrosis ,Chiroptera ,medicine ,Animals ,education ,Hemochromatosis ,education.field_of_study ,General Veterinary ,biology ,medicine.diagnostic_test ,Transferrin saturation ,General Medicine ,medicine.disease ,biology.organism_classification ,Ferritin ,Liver ,Ferritins ,biology.protein ,Serum iron ,Animals, Zoo ,Female ,Animal Science and Zoology ,Histopathology ,Rousettus ,Blood Chemical Analysis - Abstract
This study evaluated the relationship between blood iron parameters and hepatic iron concentrations, and correlation of histologic findings with hepatic iron concentrations in a captive population of Egyptian fruit bats (Rousettus aegyptiacus) and island flying foxes (Pteropus hypomelanus). Blood samples were collected for complete blood counts, plasma biochemical profiles, serum iron concentrations, total iron-binding capacity, whole-blood lead concentrations, and plasma ferritin assays. Liver samples obtained by laparotomy were divided, with one half processed for histologic examination and the other half frozen and submitted for tissue mineral analysis. The histologic sections were scored by two blinded observers for iron deposition, necrosis, and fibrosis. The Egyptian fruit bats had significantly higher liver iron (mean = 3,669 +/- 1,823 ppm) and lead (mean = 8.9 +/- 5.8 ppm) concentrations than the island flying foxes (mean [Fe] = 174 +/- 173 ppm, mean [Pb] = 1.9 +/- 0.5 ppm). Hepatic iron concentrations significantly correlated with tissue lead concentrations, histologic grading for iron and necrosis, serum iron, transferrin saturation, and plasma ferritin (P < 0.001). Blood lead concentrations negatively correlated with tissue lead concentrations (P < 0.001). When the product of transferrin saturation and serum iron was greater than 51, an individual animal had a high probability of having iron overload. When the product of these two variables was greater than 90, there was a high probability that the animal had hemochromatosis. On the basis of this study, it appears that evaluation of serum iron, transferrin saturation, and plasma ferritin are useful and noninvasive methods for diagnosis of hemochromatosis in Egyptian fruit bats.
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- 2005
13. DERMATOPHILUS CHELONAE IN A KING COBRA (OPHIOPHAGUS HANNAH)
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Carol J. Detrisac, James F. X. Wellehan, Jeffrey J. O'Kelley, Christine Turenne, and Darryl J. Heard
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Male ,SUBCUTANEOUS MASS ,Pathology ,medicine.medical_specialty ,King cobra ,Cobra ,Dermatophilus chelonae ,Antibiotic therapy ,Actinomycetales ,Surgical site ,medicine ,Animals ,Elapidae ,computer.programming_language ,General Veterinary ,biology ,Left flank ,Skin Diseases, Bacterial ,General Medicine ,biology.organism_classification ,Anti-Bacterial Agents ,Treatment Outcome ,Animal Science and Zoology ,Granulomatous Dermatitis ,Actinomycetales Infections ,computer - Abstract
A mass was removed from the left flank of a 10-yr-old male king cobra (Ophiophagus hannah), and histologic examination revealed granulomatous dermatitis with intralesional gram-positive cocci and filamentous bacteria. Fourteen months later, a histologically similar subcutaneous mass was removed from a different site. One year later, a large subcutaneous mass at the first surgical site was removed, and histopathologic examination revealed multiloculated granulomas with intralesional gram-positive cocci. An organism was cultured and identified by 16S ribosomal RNA gene sequencing as Dermatophilus chelonae. After a course of antibiotic therapy, no further lesions were seen for 5 mo.
- Published
- 2004
14. Functional Characterization of a Recombinant Adeno- Associated Virus 5-Pseudotyped Cystic Fibrosis Transmembrane Conductance Regulator Vector
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Thomas W. Ferkol, Christian Muller, Hungwen Yue, Qiushi Tang, Carol J. Detrisac, Jeffrey Sirninger, Terence R. Flotte, Sofia Braag, and William B. Guggino
- Subjects
Cystic Fibrosis ,viruses ,Genetic enhancement ,Genetic Vectors ,DNA, Recombinant ,Cystic Fibrosis Transmembrane Conductance Regulator ,Gene Expression ,medicine.disease_cause ,Recombinant virus ,Virus ,Mice ,Chloride Channels ,Weight Loss ,Genetics ,medicine ,Animals ,Cloning, Molecular ,Luciferases ,Promoter Regions, Genetic ,Enhancer ,Molecular Biology ,Adeno-associated virus ,Rous sarcoma virus ,biology ,Promoter ,Genetic Therapy ,Pneumonia ,Dependovirus ,biology.organism_classification ,Virology ,Molecular biology ,Actins ,Cystic fibrosis transmembrane conductance regulator ,Pseudomonas aeruginosa ,biology.protein ,Molecular Medicine - Abstract
Despite extensive experience with recombinant adeno-associated virus (rAAV) 2 vectors in the lung, gene expression has been low in the context of cystic fibrosis (CF) gene therapy, where the large size of the cystic fibrosis transmembrane conductance regulator (CFTR) coding sequence has prompted the use of compact endogenous promoter elements. We evaluated the possibility that gene expression from recombinant adeno-associated virus (rAAV) could be improved by using alternate AAV capsid serotypes that target different cell-surface receptors (i.e., rAAV5) and/or using stronger promoters. The relative activities of the cytomegalovirus (CMV) Rous sarcoma virus (RSV) promoter, the CMV enhancer/beta-actin (CB) promoter combination, and the CMV enhancer/RSV promoter hybrid were assessed in vitro in a CF bronchial cell line. The CB promoter was the most efficient. AAV capsid serotypes, rAAV2 and rAAV5, were also compared, and rAAV5 was found to be significantly more efficient. Based on these studies a rAAV5-CB-promoter-driven CFTR minigene vector was then used to correct the CF chloride transport defect in vitro, as well as the hyperinflammatory lung phenotype in Pseudomonas-agarose bead challenged CF mouse lungs in vivo. These studies provide functional characterization of a new version of rAAV-CFTR vectors.
- Published
- 2004
15. Periocular sarcoid in a horse
- Author
-
Carol J. Detrisac, Stacy E. Andrew, Dennis Brooks, András M. Komáromy, and Kirk N. Gelatt
- Subjects
Antitumor activity ,medicine.medical_specialty ,Pathology ,Sarcoidosis ,General Veterinary ,medicine.diagnostic_test ,business.industry ,Horse ,Computed tomography ,Injections, Intralesional ,Eyelid Neoplasms ,eye diseases ,Surgery ,Diagnosis, Differential ,BCG Vaccine ,medicine ,Animals ,Periocular Region ,Female ,Horse Diseases ,Horses ,sense organs ,Tomography, X-Ray Computed ,business - Abstract
A periocular nodular sarcoid of the right upper and lower eyelids was diagnosed in an 11-year-old Thoroughbred mare. Computed tomography scan revealed the extent of the tumor. The mass was surgically debulked under general anesthesia, and the affected periocular region was injected intralesionally with Bacillus of Calmette and Guerin (BCG). An emulsion of cell wall fractions was used, which has been modified to reduce the toxic and allergic effect, but retain the antitumor activity. In total, five injections were performed at 2-week intervals. At follow-up 7 months after the last BCG injection, the tumor was completely resolved. Two years after the last treatment, the horse remains tumor-free.
- Published
- 2004
16. Effect of thalidomide on growth and metastasis of canine osteosarcoma cells after xenotransplantation in athymic mice
- Author
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Leslie E. Fox, James M. Van Gilder, Carol J. Detrisac, Jamie M Baldwin, James P. Farese, and Sara L. Roberts
- Subjects
Pathology ,medicine.medical_specialty ,Lung Neoplasms ,Time Factors ,Xenotransplantation ,medicine.medical_treatment ,Mice, Nude ,Angiogenesis Inhibitors ,Pharmacology ,Canine Osteosarcoma ,Metastasis ,Mice ,Dogs ,Tumor Cells, Cultured ,medicine ,Animals ,Dimethyl Sulfoxide ,Dog Diseases ,Osteosarcoma ,Dose-Response Relationship, Drug ,General Veterinary ,Tumor size ,business.industry ,General Medicine ,medicine.disease ,Thalidomide ,Drug vehicle ,Female ,business ,Neoplasm Transplantation ,medicine.drug - Abstract
Objective—To determine whether thalidomide inhibits the growth of primary and pulmonary metastatic canine osteosarcoma in mice after xenotransplantation. Animals—Athymic nude mice. Procedure—Canine osteosarcoma cells were injected SC in 50 mice. Mice were randomly placed into the following groups: control group (n = 13; DMSO [drug vehicle] alone [0.1 mL/d, IP]); low-dose group (12; thalidomide [100 mg/kg, IP]), mid-dose group (13; thalidomide [200 mg/kg, IP]); and high-dose group (12; thalidomide [400 mg/kg, IP]). Starting on day 8, treatments were administered daily and tumor measurements were performed for 20 days. On day 28, mice were euthanatized and primary tumors were weighed. Lungs were examined histologically to determine the number of mice with metastasis and tumor emboli. Mean area of the pulmonary micrometastatic foci was determined for mice from each group. Results—Primary tumor size and weight were not significantly different among groups. The number of mice in the mid-dose (200 mg/kg) and high-dose (400 mg/kg) groups with micrometastasis was significantly less than the number of control group mice; however, the number of mice with tumor emboli was not affected by thalidomide treatment. Size of micrometastasis lesions was not affected by thalidomide treatment. Conclusions and Clinical Relevance—Mean area of micrometastases was not affected by treatment; however, growth of micrometastases had not yet reached an angiogenesis-dependent size. Although thalidomide did not affect growth of primary tumors in mice after xenotransplantation of canine osteosarcoma cells, our findings indicate that thalidomide may interfere with the ability of embolic tumor cells to complete the metastatic process within the lungs. ( Am J Vet Res 2004;65:659–664)
- Published
- 2004
17. AN EPIZOOTIC OF CHRONIC REGURGITATION ASSOCIATED WITH CHLAMYDOPHILOSIS IN RECENTLY IMPORTED EMERALD TREE BOAS (CORALLUS CANINUS)
- Author
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Elliott R. Jacobson, Darryl J. Heard, Carol J. Detrisac, and Brad Lock
- Subjects
Pathology ,medicine.medical_specialty ,Time Factors ,Lymphocytosis ,Population ,Animals, Wild ,Monocytosis ,Cause of Death ,Prevalence ,medicine ,Animals ,Leukocytosis ,education ,Chlamydophila Infections ,Epizootic ,Antigens, Bacterial ,education.field_of_study ,General Veterinary ,biology ,Chlamydophila ,Incidence (epidemiology) ,General Medicine ,medicine.disease ,biology.organism_classification ,Immunohistochemistry ,Corallus caninus ,Boidae ,Regurgitation (digestion) ,Gastroesophageal Reflux ,Animal Science and Zoology ,medicine.symptom - Abstract
One hundred and five wild-caught emerald tree boas (Corallus caninus) were added to a collection of 15 others. in Central Florida, during a 4-mo period. Eighty-one boas (67%) developed repetitive regurgitation during the 23-mo period after the initial introduction, and 61 (75%) of these died. Regurgitation occurred 3-4 days after feeding. Prevalence of regurgitation in this population of snakes was 25%/mo (range 0-42%), and incidence was 3.52/mo (range 0-13/mo). The cumulative mortality for those boas developing repetitive regurgitation (61 of 120) during the 23-mo epizootic was 51%. Hematologic findings included anemia and leukocytosis, with lymphocytosis, monocytosis, and azurophilia. Histologic evaluation of the gastrointestinal tract showed multifocal to diffuse lymphoplasmacytic inflammation with granuloma formation and positive immunohistochemical staining for chlamydial antigen. Electron microscopic evaluation of granulomas showed organisms consistent with Chlamydophila sp.
- Published
- 2003
18. SONOGRAPHIC AND SCINTIGRAPHIC EVALUATION OF ACUTE RENAL ALLOGRAFT REJECTION IN CATS
- Author
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Frank G. Martin, Krista B. Halling, Gary W. Ellison, Daniel Grossman, James M. VanGilder, John P. Graham, Carol J. Detrisac, and Susan P. Newell
- Subjects
Graft Rejection ,Male ,medicine.medical_specialty ,medicine.medical_treatment ,Urology ,Diastole ,Renal function ,Kidney ,Kidney Function Tests ,urologic and male genital diseases ,Renal Circulation ,medicine ,Animals ,Radionuclide Imaging ,Ultrasonography ,Renal circulation ,CATS ,General Veterinary ,business.industry ,Echogenicity ,Blood flow ,Kidney Transplantation ,Nephrectomy ,Specific Pathogen-Free Organisms ,Surgery ,medicine.anatomical_structure ,Cats ,Prednisolone ,Technetium Tc 99m Pentetate ,business ,Glomerular Filtration Rate ,medicine.drug - Abstract
The sonographic features of acute renal allograft rejection in humans and dogs are manifested by increase in renal cross-sectional area and reduction in renal cortical blood flow. These changes have not been investigated in cats. The objectives of this study were to evaluate sonographic and scintigraphic changes during acute renal allograft rejection in cats. Eight SPF, intact, adult, male cats received heterotopic renal allotransplantations. Immunosuppressive doses of cyclosporine and prednisolone were administered for 14 days and then discontinued to allow acute allograft rejection to occur. Serial measurements of renal cross-sectional area, resistive index (RI), echogenicity, and glomerular filtration rate (GFR) were performed to evaluate changes during acute rejection. Upon sonographic confirmation of absent diastolic blood flow or a 20% increase in cross-sectional area of the allograft, a nephrectomy and histopathologic evaluation were performed. Acute allograft rejection was confirmed histologically in all cats. Significant increases in renal cross-sectional area (P < 0.001) occurred postoperatively and during rejection. There were no significant changes in RI (P = 0.43) at any time. A subjective increase in medullary echogenicity and a decrease in corticomedullary demarcation were observed in the rejection period. While GFR decreased significantly in the immediate postoperative period (P < 0.001), no further change occurred during rejection (P = 0.42). Changes in RI and GFR do not appear to be sensitive indicators of acute renal allograft rejection in cats. Serial measurements of renal cross-sectional area appear to be a sensitive method for the early diagnosis of allograft rejection in feline renal transplant recipients.
- Published
- 2003
19. Clinical Evaluation of Rabies Virus Meningoencephalomyelitis in a Dog
- Author
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Lisa L. Farina, Cheryl L. Chrisman, Carol J. Detrisac, and Heidi L Barnes
- Subjects
Pathology ,medicine.medical_specialty ,Rabies ,Lymphocytic pleocytosis ,Fluorescent Antibody Technique ,Electromyography ,medicine.disease_cause ,Dogs ,Fatal Outcome ,Meningoencephalitis ,medicine ,Paralysis ,Animals ,Dementia ,Dog Diseases ,Small Animals ,Direct fluorescent antibody ,Paraplegia ,medicine.diagnostic_test ,business.industry ,Rabies virus ,Hyperesthesia ,medicine.disease ,body regions ,Anesthesia ,Female ,medicine.symptom ,business - Abstract
A 6-month-old, female, mixed-breed dog presented for acute, progressive, flaccid paraplegia and bilateral pelvic-limb hyperesthesia. A lymphocytic pleocytosis with 366 mg/dL protein was found on cerebral spinal fluid (CSF) evaluation. Electromyography (EMG) demonstrated positive sharp waves and fibrillations in the left pelvic limb; the M wave of the left sciatic nerve was not obtainable by nerve stimulation. Seizures and dementia began during recovery from anesthesia. Six days after onset of paralysis, the dog was euthanized. Direct fluorescent antibody testing of the brain was positive for raccoon rabies virus. This case demonstrates clinical evaluation, CSF analysis, and EMG in an animal with rabies meningoencephalomyelitis.
- Published
- 2003
20. Clinicopathologic Findings Associated withLagenidiumsp. Infection in 6 Dogs: Initial Description of an Emerging Oomycosis
- Author
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Carol J. Detrisac, Nadine R. Znajda, Rudy W. Bauer, Randall C. Thomas, E. Clay Hodgin, and Amy M. Grooters
- Subjects
Male ,Pathology ,medicine.medical_specialty ,Lagenidium ,Blotting, Western ,Infections ,Pythium insidiosum ,Pythiosis ,Dogs ,Eosinophilic ,medicine ,Animals ,Dog Diseases ,Antigens ,Skin Diseases, Infectious ,Lymphatic Diseases ,General Veterinary ,biology ,business.industry ,Thrombosis ,Anatomy ,biology.organism_classification ,medicine.disease ,Lymphatic disease ,Subcutaneous nodule ,Giant cell ,Female ,Zygomycosis ,business - Abstract
An oomycotic pathogen in the genus Lagenidium was isolated from tissues obtained from 6 dogs with progressive cutaneous disease. Initial clinical findings in 5 dogs included multifocal cutaneous lesions, subcutaneous lesions, or both associated with regional lymphadenopathy: the 6th dog initially was presented for evaluation of mandibular lymphadenopathy. Cutaneous lesions were ulcerated, exudative regions (often with necrosis and draining tracts) or multiple firm dermal or subcutaneous nodules. Two dogs subsequently developed hemoabdomen from great vessel rupture and died acutely. Four dogs were euthanized because of progression of subcutaneous lesions or lymphadenopathy. On postmortem examination, regional granulomatous lymphadenitis was found in all 6 dogs, great vessel invasion in 3 dogs, pulmonary lesions in 2 dogs. ureteral obstruction in 1 dog, mediastinal lymphadenitis in 1 dog, and hilar lymphadenitis with invasion of the distal esophagus and trachea in 1 dog. Histologically, lesions were similar to those associated with pythiosis and zygomycosis and were characterized by severe eosinophilic granulomatous inflammation (often with numerous large multinucleated giant cells) centered around broad (7-25 micro), infrequently septate hyphae. Immunoblot analysis of the serologic response of 4 dogs to a soluble mycelial extract of Lagenidium giganteum indicated that each dog's serum recognized at least 10 different antigens of L. giganteum. Culture of infected tissues yielded rapid growth of colorless to white submerged colonies. Microscopically, mature hyphae in culture were broad (25-40 micro), segmented, and occasionally branching and produced motile laterally biflagellate zoospores in water culture. This report is the 1st description of infection caused by an oomycete other than Pythium insidiosum in any mammalian species.
- Published
- 2003
21. West Nile Virus encephalomyelitis in horses: 46 cases (2001)
- Author
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Steeve Giguère, Michael B. Porter, Guy D. Lester, Robert J. MacKay, Claus D Buergelt, Carol J. Detrisac, Stephanie Jacks, Liberty M. Getman, A Richard Alleman, Robert P. Franklin, Heather L. Wamsley, and Maureen T. Long
- Subjects
Male ,medicine.medical_specialty ,Ataxia ,Encephalomyelitis ,Serology ,Diagnosis, Differential ,Sex Factors ,Plaque reduction neutralization test ,Internal medicine ,medicine ,Animals ,Clinical significance ,Horses ,Retrospective Studies ,Paresis ,General Veterinary ,business.industry ,Mortality rate ,Horse ,medicine.disease ,Treatment Outcome ,Immunology ,Female ,Horse Diseases ,medicine.symptom ,business ,West Nile virus ,West Nile Fever - Abstract
Objective—To determine signalment, clinical findings, results of diagnostic testing, outcome, and postmortem findings in horses with West Nile virus (WNV) encephalomyelitis. Design—Retrospective study. Animals—46 horses with WNV encephalomyelitis. Procedure—Clinical data were extracted from medical records of affected horses. Results—On the basis of clinical signs and results of serologic testing, WNV encephalomyelitis was diagnosed in 46 of 56 horses with CNS signs. Significantly more males than females were affected. Increased rectal temperature, weakness or ataxia, and muscle fasciculations were the most common clinical signs. Paresis was more common than ataxia, although both could be asymmetrical and multifocal. Supportive treatment included anti-inflammatory medications, fluids, antimicrobials, and slinging of recumbent horses. Results of the IgM capture ELISA and the plaque reduction neutralization test provided a diagnosis in 43 horses, and only results of the plaque reduction neutralization test were positive in 3 horses. Mortality rate was 30%, and 71% of recumbent horses were euthanatized. One horse that had received 2 vaccinations for WNV developed the disease and was euthanatized. Follow-up communications with 19 owners revealed that most horses had residual deficits at 1 month after release from the hospital; abnormalities were resolved in all but 2 horses by 12 months after release. Conclusions and Clinical Relevance—Our findings were similar to those of previous WNV outbreaks in horses but provided additional clinical details from monitored hospitalized horses. Diagnostic testing is essential to diagnosis, treatment is supportive, and recovery rate of discharged ambulatory horses is < 100%. (J Am Vet Med Assoc 2003;222:1241–1247)
- Published
- 2003
22. Tissue Culture of Human Renal Epithelial Cells Using a Defined Serum-Free Growth Formulation
- Author
-
Sharon L. Wenger, Carol J. Detrisac, Michael R. Rossi, Mary Ann Sens, Donald A. Sens, and John H. Todd
- Subjects
Pathology ,medicine.medical_specialty ,Kidney Cortex ,Physiology ,Cellular differentiation ,Cell Culture Techniques ,Biology ,Arginine ,Kidney ,Wilms Tumor ,Culture Media, Serum-Free ,Kidney Tubules, Proximal ,chemistry.chemical_compound ,Tissue culture ,1-Methyl-3-isobutylxanthine ,Cyclic AMP ,Genetics ,medicine ,Freeze Fracturing ,Humans ,Microscopy, Phase-Contrast ,Carcinoma, Renal Cell ,Growth medium ,Effector ,Cell Differentiation ,Epithelial Cells ,General Medicine ,Embryo, Mammalian ,Kidney Neoplasms ,Epithelium ,Cell biology ,Microscopy, Electron ,medicine.anatomical_structure ,chemistry ,Parathyroid Hormone ,Nephrology ,Cell culture ,Cell Division ,Hormone - Abstract
Background: Development of the culture of renal epithelial cells in a serum-free growth medium was driven by the need to examine the effects of hormones and other effector molecules on differentiated cell function without interference from the complex mixture of substances in serum. The present report details this laboratory’s cumulative experience in the use of a defined growth medium for the propagation of epithelial cells from adult, fetal, and malignant human renal tissue. Methods: Routine cell culture technology was used to determine the capability of a defined growth medium to support the growth of renal epithelial cells isolated by collagenase dissociation of tissue from adult and fetal kidneys, renal cell carcinoma, and Wilms’ tumors. Results: The defined growth medium formulation consistently allows the isolation and growth of transporting renal epithelial cells from both normal adult and fetal kidneys. This growth medium only rarely supports the growth of epithelial cells from renal cell carcinomas and Wilms’ tumors. Conclusions: The method developed for the culture of human proximal tubule cells requires minimal cell culture expertise and equipment, and results in the repeatable isolation of transporting epithelial cell cultures that retain features of differentiated proximal tubule cells.
- Published
- 1999
23. MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION: Differential activity of aspirin, ketoprofen and sulindac as cancer chemopreventive agents in the mouse urinary bladder
- Author
-
David L. McCormick, Gary J. Kelloff, Ernest T. Hawk, K.V.N. Rao, Vernon E. Steele, and Carol J. Detrisac
- Subjects
Ketoprofen ,Cancer Research ,Sulindac ,Aspirin ,Bladder cancer ,Urinary bladder ,business.industry ,Cancer ,General Medicine ,Pharmacology ,medicine.disease ,medicine.anatomical_structure ,Transitional cell carcinoma ,medicine ,business ,Anticarcinogen ,medicine.drug - Abstract
In vivo studies were conducted to compare the activity of three non-steroidal anti-inflammatory drugs as inhibitors of urinary bladder carcinogenesis induced in B6D2F1 (BDF) mice by N-butyl-N-(4-hydroxybutyl)nitrosamine (OH-BBN). Mice received continuous dietary exposure to non-toxic doses of aspirin, sulindac or ketoprofen beginning 1 week prior to the first of eight weekly doses of 7.5 mg OH-BBN; studies were terminated at 24 weeks after the first carcinogen dose. Both dose levels of sulindac (200 and 400 mg/kg diet) and both dose levels of ketoprofen (40 and 80 mg/kg diet) reduced the incidence of transitional cell carcinoma of the urinary bladder by >70% from that seen in dietary controls. The high dose of sulindac conferred the greatest protection against bladder cancer induction. In contrast, when administered at 400 and 800 mg/kg diet aspirin was inactive as a chemopreventive agent in the OH-BBN/BDF bladder cancer model. The significant potency of sulindac and ketoprofen as inhibitors of urinary bladder carcinogenesis, when considered with their history of safe human use, suggests that these agents merit further study as drugs for cancer chemoprevention in this target tissue.
- Published
- 1996
24. Toxicologic evaluation of tungsten: 28-day inhalation study of tungsten blue oxide in rats
- Author
-
Shu-Chieh Hu, Dennis Sullivan, Carol J. Detrisac, Carmen Venezia, Narayanan Rajendran, and Miguel Muzzio
- Subjects
Male ,Metabolic Clearance Rate ,Health, Toxicology and Mutagenesis ,Oxide ,chemistry.chemical_element ,Pharmacology ,Tungsten ,Toxicology ,Kidney ,Risk Assessment ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,In vivo ,Macrophages, Alveolar ,medicine ,Toxicokinetics ,Animals ,Tissue Distribution ,Femur ,Particle Size ,Lung ,Aerosols ,Inhalation Exposure ,Inhalation ,Oxides ,equipment and supplies ,Rats ,medicine.anatomical_structure ,chemistry ,Anesthesia ,Area Under Curve ,Toxicity ,Female ,Particulate Matter ,Biomarkers ,Foam Cells ,Half-Life - Abstract
The toxicity and toxicokinetics of tungsten blue oxide (TBO) were examined. TBO is an intermediate in the production of tungsten powder, and has shown the potential to cause cellular damage in in vitro studies. However, in vivo evidence seems to indicate a lack of adverse effects. The present study was undertaken to address the dearth of longer-term inhalation toxicity studies of tungsten oxides by investigating the biological responses induced by TBO when administered via nose-only inhalation to rats at levels of 0.08, 0.325, and 0.65 mg TBO/L of air for 6 h/day for 28 consecutive days, followed by a 14-day recovery period. Inhaled TBO was absorbed systemically and blood levels of tungsten increased as inhaled concentration increased. Among the tissues analyzed for tungsten levels, lung, femur and kidney showed increased levels, with lung at least an order of magnitude greater than kidney or femur. By exposure day 14, tungsten concentration in tissues had reached steady-state. Increased lung weight was noted for both terminal and recovery animals and was attributed to deposition of TBO in the lungs, inducing a macrophage influx. Microscopic evaluation of tissues revealed a dose-related increase in alveolar pigmented macrophages, alveolar foreign material and individual alveolar foamy macrophages in lung. After a recovery period there was a slight reduction in the incidence and severity of histopathological findings. Based on the absence of other adverse effects, the increased lung weights and the microscopic findings were interpreted as nonadverse response to exposure and were not considered a specific reaction to TBO.
- Published
- 2012
25. Contents Vol. 7, 1999
- Author
-
Gerhard A. Müller, Mary Ann Sens, Kimberley Morrisey, M. E. De Broe, David W. Johnson, Jill T. Norman, Pat Steiner, Gérard Friedlander, Uwe de Vries, Giuseppe Remuzzi, Cees van Kooten, Gabrielle M. Hawksworth, Simonne Dauwe, Michael Field, Anna L. Trifillis, Raimund Strehl, James S. McLay, Clemens Grupp, Syed O. Huq, Pablo Bautista Garcia, Robert Steadman, Donald A. Sens, Sharon L. Wenger, John H. Todd, Ariela Benigni, M.J.F. Helbert, Marc E. De Broe, Isabelle Runembert, Leon G. Fine, Heather J. Saunders, Carol A. Pollock, Fiona J. Johnson, Fabiola Terzi, Michael R. Rossi, Leendert A. van Es, Sabine Kloth, Mark J.F. Helbert, Karl Schumacher, Carla Zoja, Carol J. Detrisac, John D. Williams, Michael B. Ganz, Will W. Minuth, Prabal K. Chatterjee, C. Orphanides, François Vrtovsnik, Mohamed R. Daha, Alain Vandewalle, and Aled O. Phillips
- Subjects
Nephrology ,Physiology ,Genetics ,General Medicine - Published
- 1999
26. Evaluation of oxidative stress markers for the early diagnosis of allograft rejection in feline renal allotransplant recipients with normal renal function
- Author
-
Krista B, Halling, Gary W, Ellison, Don, Armstrong, Kasumi, Aoyagi, Carol J, Detrisac, John P, Graham, Susan P, Newell, Frank G, Martin, and James M, Van Gilder
- Subjects
Graft Rejection ,Male ,Fever ,Scientific ,Cat Diseases ,Kidney ,Kidney Function Tests ,Kidney Transplantation ,Thiobarbituric Acid Reactive Substances ,Specific Pathogen-Free Organisms ,Oxidative Stress ,Predictive Value of Tests ,Creatinine ,Cats ,Animals ,Kidney Failure, Chronic ,Lactic Acid ,Biomarkers ,Ultrasonography - Abstract
The purpose of this study was to identify oxidative damage to renal allografts during graft rejection by evaluating changes in oxidative markers and plasma lactate levels in feline renal allotransplant recipients. Heterotopic renal allotransplantations were performed between 8 adult feline cross-matched donors. Following 14 d of immunosuppression, the drugs were discontinued to allow allograft rejection. Baseline and serial postoperative evaluations of serum creatinine, plasma lactate, plasma thiobarbituate reactive substances (TBARS), plasma creatol, urine creatol, and renal sonographic cross-sectional area were performed. When sonographic evaluation revealed the absence of blood flow to the allograft, the rejected kidney was nephrectomized and evaluated histopathologically. Allograft rejection occurred in all cats by day 26. A significant elevation in body temperature occurred during the rejection period. No significant change was observed between any of the time periods for plasma TBARS, creatol, or urine creatol. There was a significant decrease in plasma lactate levels throughout the study. Markers of oxidative stress from venous blood did not reflect renal allograft rejection in cats with a normally functioning native kidney. Renal allograft rejection may be associated with significant increases in body temperature and warrants further investigation.
- Published
- 2004
27. Varanid herpesvirus 1: a novel herpesvirus associated with proliferative stomatitis in green tree monitors (Varanus prasinus)
- Author
-
Douglas P. Whiteside, James F. X. Wellehan, Scott P. Terrell, April J. Johnson, Carol J. Detrisac, Darryl J. Heard, Graham J. Crawshaw, April L. Childress, Kenneth S. Latimer, and Elliott R. Jacobson
- Subjects
Subfamily ,Sequence analysis ,DNA polymerase ,Molecular Sequence Data ,In situ hybridization ,medicine.disease_cause ,Microbiology ,Polymerase Chain Reaction ,Virus ,Herpesviridae ,parasitic diseases ,medicine ,Varanus prasinus ,Animals ,Stomatitis ,Phylogeny ,General Veterinary ,biology ,Base Sequence ,Mouth Mucosa ,Nucleic Acid Hybridization ,Lizards ,General Medicine ,Herpesviridae Infections ,medicine.disease ,biology.organism_classification ,Virology ,body regions ,Stomatitis, Herpetic ,DNA, Viral ,biology.protein ,Female ,sense organs - Abstract
Stomatitis is a common problem in lizards, and the etiologies of stomatitis in lizards are not well understood. Four green tree monitor lizards (Varanus prasinus) from two different collections were evaluated because of proliferative stomatitis. Degenerate PCR primers targeting a conserved region of herpesvirus DNA-dependent DNA polymerase were used to amplify and sequence a product from gingival tissue of three of four lizards (cases 1, 3, and 4). DNA in situ hybridization of tissues from three lizards was positive for herpesvirus in the oral mucosa of all three lizards tested (cases 1–3) and the brain of two lizards (cases 1 and 3). Comparative sequence analysis suggests that this virus is a novel member of the subfamily a-herpesvirinae, and is here termed varanid herpesvirus 1. # 2004 Elsevier B.V. All rights reserved.
- Published
- 2004
28. Efficacy of mitoxantrone-loaded albumin microspheres for intratumoral chemotherapy of breast cancer
- Author
-
Brett A. Almond, Ahmad Robert Hadba, Brian J. Cuevas, Eugene P. Goldberg, Amanda M. York, Carol J. Detrisac, and Shema T. Freeman
- Subjects
Drug ,medicine.drug_class ,media_common.quotation_subject ,medicine.medical_treatment ,Pharmaceutical Science ,Antineoplastic Agents ,Pharmacology ,Adenocarcinoma ,Antimetabolite ,Dosage form ,Mice ,In vivo ,Albumins ,medicine ,Animals ,media_common ,Chemotherapy ,Mitoxantrone ,Mice, Inbred C3H ,business.industry ,Body Weight ,Mammary Neoplasms, Experimental ,Survival Analysis ,Microspheres ,Toxicity ,Microscopy, Electron, Scanning ,Female ,Drug carrier ,business ,medicine.drug - Abstract
Systemic toxicity of intravenously delivered chemotherapy is a limiting factor in the treatment of many cancers. We have shown that intratumoral injection of antineoplastic drugs can provide high localized drug concentrations with greatly reduced systemic toxicity. Using albumin microspheres as a drug carrier, localized and sustained release of chemotherapeutic drugs has been achieved by intratumoral injection, thus increasing the intratumoral dose and antitumor efficacy. Microspheres provide the advantages of localized, prolonged drug release. The efficacy and toxicity of intratumoral free mitoxantrone or mitoxantrone-loaded albumin microspheres were evaluated in a murine breast cancer model. In the same model, a combination of these two therapies was also evaluated. Results indicated that intratumoral mitoxantrone, especially in microsphere preparations, significantly improved survival and decreased systemic toxicity.
- Published
- 2003
29. Immunohistochemical staining of chlamydial antigen in emerald tree boas (Corallus caninus)
- Author
-
Darryl J. Heard, Elliott R. Jacobson, Francesco C. Origgi, and Carol J. Detrisac
- Subjects
0301 basic medicine ,Pathology ,medicine.medical_specialty ,040301 veterinary sciences ,Biology ,0403 veterinary science ,03 medical and health sciences ,Antigen ,medicine ,Animals ,Chlamydia ,Antigens, Bacterial ,Granuloma ,General Veterinary ,Antibodies, Monoclonal ,04 agricultural and veterinary sciences ,Chlamydia Infections ,medicine.disease ,biology.organism_classification ,Immunohistochemistry ,Staining ,Basophilic ,Corallus caninus ,Boidae ,030104 developmental biology ,medicine.anatomical_structure ,Liver ,Tonsil ,biology.protein ,Antibody - Abstract
Of 120 privately owned captive-bred and wild-collected emerald tree boas (ETBs) ( Corallus caninus), 97 died or were euthanatized. Eighteen snakes were necropsied, and tissues were collected from all major organs and processed for light microscopy. Histologic examination demonstrated histiocytic granulomas in the small intestine, heart, and esophageal tonsils of one ETB, small intestine of a second ETB, and in an esophageal tonsil of a third ETB. Within the center of these granulomas, small, basophilic, punctate organisms were demonstrated using hematoxylin and eosin staining. Transmission electron microscopic examination of an intestinal granuloma demonstrated developmental stages of organisms consistent with members of the family Chlamydiaceae. An immunoperoxidase staining technique and 2 different commercially available monoclonal antibodies against chlamydial lipopolysaccharide antigen was used to identify chlamydial antigen in these lesions. Liver of a puff adder ( Bitis arietans) with previously reported systemic chlamydiosis served as the positive control. Both monoclonal antibodies stained antigen in these granulomas. Additionally, macrophages within aggregates of lymphoplasmacytic cells in the colon, small intestine, and esophageal tonsils of 3 other ETBs contained antigen. Although both antibodies labeled antigen in serial sections of tissue, a difference in staining intensity was noted.
- Published
- 2002
30. Use of a high-molecular-weight carboxymethylcellulose in a tissue protective solution for prevention of postoperative abdominal adhesions in ponies
- Author
-
Carol J. Detrisac, Lynn S. Peck, Christopher W. Widenhouse, David J. Murphy, and Eugene P. Goldberg
- Subjects
Male ,medicine.medical_specialty ,medicine.medical_treatment ,Abrasion (medical) ,Tissue Adhesions ,Peritoneal Diseases ,Postoperative Complications ,Laparotomy ,Abdomen ,medicine ,Animals ,Horses ,Abdominal adhesions ,General Veterinary ,business.industry ,Peritoneal fluid ,General Medicine ,medicine.disease ,Surgery ,Molecular Weight ,Solutions ,Anesthesia ,Carboxymethylcellulose Sodium ,Female ,Horse Diseases ,business ,Jejunal serosa - Abstract
Objective—To evaluate efficacy and safety of IP administration of high-molecular-weight carboxymethylcellulose (HMW CMC) for the prevention of postoperative intra-abdominal adhesions in ponies. Animals—10 ponies. Procedure—A 1% solution of HMW CMC was instilled intra-abdominally prior to surgery in 5 ponies, whereas 5 control ponies did not receive HMW CMC. Postoperative adhesions were induced by use of a bowel-abrasion method comprising laparotomy, typhlotomy, and abrasion of jejunal serosa at multiple sites with placement of 3 sutures at each site. Day of surgery was day 0. After surgery, ponies were monitored, and hematologic, serum biochemical, and peritoneal fluid analyses were performed on days 1, 2, 3, 5, 7, and 10. On day 10, ponies were euthanatized. Intra-abdominal adhesions were recorded, and tissue samples were collected for histologic examination. Results—A significantly greater number of adhesions, number of multiple adhesions, and mean incidence of adhesions were identified in control ponies, compared with CMC-treated ponies. Mean peritoneal fluid WBC count on day 7 and serum fibrinogen concentrations on days 5 and 7 were significantly higher in control ponies, compared with CMC-treated ponies. Results of serum biochemical analyses did not differ significantly between the 2 groups. Conclusions and Clinical Relevance—Intra-abdominal use of 1% HMW CMC during surgery was effective for preventing postoperative adhesions in ponies. Use of HMW CMC did not have detrimental effects on wound healing, intra-abdominal defenses, or patient health. A 1% solution of HMW CMC may be used routinely during abdominal surgery of horses for prevention of postoperative adhesions. (Am J Vet Res 2002;63:1448–1454)
- Published
- 2002
31. Chemoprevention of OH-BBN-induced bladder cancer in mice by piroxicam
- Author
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Vernon E. Steele, Gary J. Kelloff, Richard C. Moon, Carol J. Detrisac, Cathy F. Thomas, and Caroline C. Sigman
- Subjects
Male ,Cancer Research ,medicine.medical_specialty ,Eflornithine ,Fenretinide ,Piroxicam ,chemistry.chemical_compound ,Mice ,Oral administration ,Internal medicine ,medicine ,Animals ,Anticarcinogen ,Carcinogen ,Carcinoma, Transitional Cell ,Urinary bladder ,Bladder cancer ,business.industry ,Drug Synergism ,General Medicine ,medicine.disease ,medicine.anatomical_structure ,Endocrinology ,Transitional cell carcinoma ,chemistry ,Urinary Bladder Neoplasms ,Nitrosamine ,Butylhydroxybutylnitrosamine ,business ,medicine.drug - Abstract
Piroxicam inhibited induction of transitional cell carcinoma in mouse urinary bladder by N-butyl-N-(4-hydroxybutyl)-nitrosamine. At 15 mg piroxicam/kg diet, tumor incidence was reduced 82% (P < 0.0001) compared with carcinogen controls. At 30 mg piroxicam/kg diet, tumor incidence was reduced 70% (P < 0.001). Results at the higher dose level suggested that piroxicam also may have inhibited invasion slightly. Combination treatment with 2-difluoromethyl-ornithine (DFMO) or all-trans-N-(4-hydroxyphenyl)retinamide (4-HPR) or both agents did not improve the chemopreventive potential of piroxicam. However, the three-agent combination of 30 mg piroxicam/kg, 1200 mg DFMO/kg and 313 mg 4-HPR/kg diet was highly effective. Tumor incidence was reduced 91% (P < 0.0001) compared with carcinogen controls. Unfortunately, the high efficacy was somewhat compromised by a significant decrease in survival and body weight gain in mice receiving the combination of agents compared with the carcinogen control.
- Published
- 1993
32. Hamster Lung Cancer Model of Carcinogenesis and Chemoprevention
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K.V.N. Rao, Carol J. Detrisac, Richard C. Moon, and Gary J. Kelloff
- Subjects
Oncology ,medicine.medical_specialty ,Inhalation ,Chemistry ,Intratracheal instillation ,Hamster ,medicine.disease ,medicine.disease_cause ,Bronchogenic carcinoma ,Internal medicine ,medicine ,Cancer research ,Lung tumor ,Lung cancer ,Carcinogenesis ,Carcinogen - Abstract
Attempts to establish a lung cancer model in hamsters that is histologically and biochemically similar to bronchogenic carcinoma in man have had limited success (1,2). Earlier hamster and mouse studies employed methods such as thread transfixions (3, 4) and exposure to radioactive compounds either by inhalation (5) or implantation of intrabronchial pellets (6). Lung cancer models in hamsters employed by Saffiotti and his associates (7–10) required the intratracheal instillation of suspensions of a crystalline polycyclic aromatic hydrocarbon adsorbed to carrier particles of inert dust. The use of nitroso-compounds, with and without carrier dust, to induce tracheal and pulmonary lesions in hamsters has also been employed (11–15). However, the physiochemical properties of these carcinogens, such as solubility and particle size, and the nature of the carrier particles are very critical with regard to tumor induction. As a result, the feasibility of obtaining a reproducible incidence of respiratory cancer in different laboratories using these techniques appears remote. Furthermore, many of the earlier lung tumor models exhibited a very low cancer incidence and a long latency period.
- Published
- 1992
33. Chemoprevention of experimental bladder cancer
- Author
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Cathy F. Thomas, Richard C. Moon, Carol J. Detrisac, and Gary J. Kelloff
- Subjects
Male ,Bladder cancer ,Sodium molybdate ,Male mice ,Antineoplastic Agents ,macromolecular substances ,Cell Biology ,Pharmacology ,Piroxicam ,medicine.disease ,Body weight ,Biochemistry ,chemistry.chemical_compound ,Transitional cell carcinoma ,chemistry ,Urinary Bladder Neoplasms ,Nitrosamine ,Oltipraz ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Animals ,Humans ,Molecular Biology ,medicine.drug - Abstract
The chemopreventive efficacy of several compounds was evaluated in the N-butyl-N-(4-hydroxybutyl)nitrosamine (OH-BBN)-induced urinary bladder cancer model using C57BL/6 x DBA/2F1 (BDF) male mice. Compounds were administered in a defined semipurified diet (AIN-76-A) either as single agents or in combination. As single agents and at the doses employed, 2-alpha-difluoromethylornithine (DFMO), piroxicam, oltipraz, and sodium molybdate effectively inhibited the incidence of transitional cell carcinoma (TCC). 4-Hydroxyphenyl retinamide (4-HPR) was ineffective. Body weight gain and survival was not affected by the doses of agents used. Combinations of two agents which increased efficacy were 4-HPR+DFMO, DFMO+piroxicam, 4-HPR+oltipraz, and DFMO+oltipraz. Three-agent combinations which showed enhanced efficacy against TCC induction were 4-HPR+Na molybdate+DFMO, 4-HPR+DFMO+piroxicam, and 4-HPR+DFMO+oltipraz. Although the three-agent combinations were, for the most part, no more effective than the two-agent combinations at the doses employed, all combination regimens significantly reduced bladder cancer incidence even when single agent administration did not.
- Published
- 1992
34. Subject Index Vol. 7, 1999
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Karl Schumacher, Leendert A. van Es, Syed O. Huq, Leon G. Fine, Heather J. Saunders, Sabine Kloth, Michael B. Ganz, Marc E. De Broe, Pablo Bautista Garcia, Giuseppe Remuzzi, Will W. Minuth, Michael Field, Kimberley Morrisey, Anna L. Trifillis, Isabelle Runembert, François Vrtovsnik, Gerhard A. Müller, Donald A. Sens, Carla Zoja, John H. Todd, M. E. De Broe, Mary Ann Sens, John D. Williams, Aled O. Phillips, Prabal K. Chatterjee, Carol J. Detrisac, Fiona J. Johnson, Jill T. Norman, Mohamed R. Daha, David W. Johnson, Raimund Strehl, C. Orphanides, Alain Vandewalle, Uwe de Vries, Robert Steadman, Pat Steiner, Cees van Kooten, Gérard Friedlander, Clemens Grupp, Ariela Benigni, Michael R. Rossi, Mark J.F. Helbert, Gabrielle M. Hawksworth, Simonne Dauwe, James S. McLay, Carol A. Pollock, Fabiola Terzi, Sharon L. Wenger, and M.J.F. Helbert
- Subjects
Index (economics) ,Nephrology ,Physiology ,Statistics ,Genetics ,Subject (documents) ,General Medicine ,Mathematics - Published
- 1999
35. Clinicopathologic Findings Associated with Lagenidium sp. Infection in 6 Dogs: Initial Description of an Emerging Oomycosis
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Amy M. Grooters, E. Clay Hodgin, Rudy W. Bauer, Carol J. Detrisac, Nadine R. Znajda, and Randall C. Thomas
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General Veterinary - Published
- 2003
36. Elevated glucose alters paracellular transport of cultured human proximal tubule cells
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John G. Blackburn, Donald A. Sens, Mary Ann Sens, Carol J. Detrisac, and Debra J. Hazen-Martin
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Cell Membrane Permeability ,Action Potentials ,Biological Transport, Active ,Biology ,In Vitro Techniques ,Kidney Tubules, Proximal ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Freeze Fracturing ,Humans ,Transcellular ,Cells, Cultured ,030304 developmental biology ,0303 health sciences ,Ussing chamber ,Tight junction ,Gap junction ,Molecular biology ,Microscopy, Electron ,medicine.anatomical_structure ,Glucose ,Intercellular Junctions ,Potential difference ,Biochemistry ,Nephrology ,030220 oncology & carcinogenesis ,Paracellular transport ,Ultrastructure ,Proximal tubule - Abstract
Elevated glucose alters paracellular transport in cultured human proximal tubule cells. Cultures of human proximal tubule cells were exposed to elevated concentrations of glucose and dome formation was assessed over a 22 day period of growth. Cultures grown on 5.5mM glucose formed five domes per microscopic field while those exposed to elevated glucose concentrations (11.0mM to 27.5mM) formed only two to three domes per field. The areas of the domes formed by the cells grown on elevated glucose concentrations were reduced as compared to those formed on 5.5mM glucose. An analysis of the electrical properties of cells grown on elevated glucose concentrations by Ussing chamber technique disclosed a marked reduction in potential difference, short circuit current, and resistance compared to cells grown on 5.5mM glucose. Routine ultrastructural analysis disclosed that cells grown on elevated glucose concentrations appeared to have fewer tight junction complexes. Further examination utilizing freeze fracture methodology demonstrated that cells grown on elevated glucose concentrations averaged two to three sealing strands per junction as compared to an average of five sealing strands for cells grown on 5.5mM glucose. The cells grown on elevated glucose concentrations were also noted to possess a greater number of gap junctions. These results demonstrate that elevated glucose concentrations can alter the paracellular route, and possibly the transcellular route, of transport regulation in cultured human proximal tubule cells.
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37. Electrophysiology and ultrastructure of cultured human proximal tubule cells
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John G. Blackburn, Carol J. Detrisac, Donald A. Sens, and Debra J. Hazen-Martin
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Pathology ,medicine.medical_specialty ,030232 urology & nephrology ,Nephron ,Kidney Tubules, Proximal ,03 medical and health sciences ,0302 clinical medicine ,Cell polarity ,medicine ,Freeze Fracturing ,Humans ,Cells, Cultured ,030304 developmental biology ,Transepithelial potential difference ,0303 health sciences ,Ussing chamber ,Tight junction ,Chemistry ,Gap junction ,Amiloride ,Cell biology ,Electrophysiology ,Microscopy, Electron ,medicine.anatomical_structure ,Cell culture ,Nephrology ,medicine.drug - Abstract
Electrophysiology and infrastructure of cultured human proximal tubule cells. The present study was undertaken to determine if cultures of human proximal tubule cells would retain in vivo properties inherent to this segment in the intact nephron. Ussing chamber studies demonstrated that these cultured cells generated transepithelial potential differences of approximately -2.0mV and resistances of 0.310 KΩ · cm 2 , supporting the concept that the proximal tubule is a "leaky" epithelium. The electrical properties did not change when the cells were exposed to amiloride (10 −4 M), but did respond to acetazolamide (10 −4 M), consistent with responses known to occur in proximal tubules. Ultrastructural analysis of these cells demonstrated features indicative of proximal tubule cells. When grown on permeable supports, where apical and basolateral growth medium compartments were maintained separate from each other; the cells were noted to undergo increased differentiation with morphological evidence of cell polarity. Freeze fracture analysis demonstrated well-formed tight junction strands and segregation of unique numbers of intramembrarious particles in apical, lateralj and basal membranes. The replicas also demonstrated the presence of aggregates thought to represent gap junctions, structures which occur exclusively in the proximal segment of the human nephron. These observations provide evidence that this human cell culture model originates from the human proximal tubule and retains, in culture, many of the properties associated with proximal tubule cell function and structure in vivo.
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38. Potentiation of vitamin A hepatotoxicity by butylated hydroxytoluene
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Carol J. Detrisac, Theresa A. Hultin, and David L. McCormick
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Vitamin ,medicine.medical_specialty ,Retinyl Esters ,Retinyl acetate ,Toxicology ,Liver weight ,Muscle hypertrophy ,chemistry.chemical_compound ,Internal medicine ,medicine ,Butylated hydroxytoluene ,Animals ,Vitamin A ,Pharmacology ,Dose-Response Relationship, Drug ,Biliary hyperplasia ,Long-term potentiation ,Drug Synergism ,Rats, Inbred Strains ,Organ Size ,Butylated Hydroxytoluene ,Fibrosis ,Rats ,Endocrinology ,chemistry ,Biochemistry ,Liver ,Female ,Diterpenes ,Hepatic fibrosis - Abstract
The interaction between the natural vitamin A ester retinyl acetate (RA) and the phenolic antioxidant butylated hydroxytoluene (BHT) in the induction of biliary hyperplasia and hepatic fibrosis in female Sprague-Dawley rats was characterized. Using a 3 × 3 matrix design, rats were fed diets supplemented with (per kilogram diet) 0, 125, or 250 mg RA and/or 0, 2500, or 5000 mg BHT. The 125-mg dose of RA induced no gross hepatotoxicity, while the 250-mg dose of RA induced a low incidence of hepatic fibrosis in rats examined after 120 and 180 days of exposure. Exposure to BHT alone induced hepatocellular hypertrophy and dose-related increases in liver weight, but no hepatocellular pathology. Simultaneous administration of RA plus BHT resulted in significant increases in the incidence of biliary hyperplasia and hepatic fibrosis compared to that induced by RA alone. BHT reduced total hepatic vitamin A content at all RA dose levels. Thus, mechanisms other than increases in liver vitamin A levels must underlie the potentiation by BHT of RA hepatotoxicity.
- Published
- 1987
39. Tissue culture of human kidney epithelial cells of proximal tubule origin
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Donald A. Sens, Samuel S. Spicer, Carol J. Detrisac, A. Julian Garvin, and Mary Ann Sens
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medicine.medical_specialty ,Kidney Cortex ,Biology ,Epithelium ,Kidney Tubules, Proximal ,Tissue culture ,chemistry.chemical_compound ,Internal medicine ,medicine ,Humans ,Cells, Cultured ,Fetus ,Confluency ,Kidney ,Growth medium ,Histocytochemistry ,Epithelial Cells ,Molecular biology ,In vitro ,Culture Media ,Endocrinology ,medicine.anatomical_structure ,Kidney Tubules ,chemistry ,Nephrology ,Proximal tubule ,Subculture (biology) - Abstract
Tissue culture of human kidney epithelial cells of proximal tubule origin. The in vitro culture of human kidney epithelial cells of defined nephronal origin would prove valuable in a variety of studies defining the factors and mechanisms responsible for diseases and disorders of the kidney. In this study we have tested the hypothesis that employing a serum-free growth medium allows the selective cultivation of human kidney epithelial cells. It is demonstrated that human kidney cortex, explanted into serum-free hormonally defined growth medium gives rise to a primary culture of kidney epithelial cells of homogenous morphology capable of hemicyst formation. While these cells were able to proliferate to confluency as an expiant culture, they were unable to undergo stable subculture. Subsequent manipulation of the culture vessel surface (an initial coat of bovine type I collagen followed by the absorption of macromolecules from fetal calf serum) yielded cultures able to be subcultured with growth to at least 30 cell generations. These cells were identified to be of proximal tubule origin by employment of enzyme histochemistry, immunohistochemistry, and ultrastructural examination. Culture tissulaire de cellules epitheliales de reins humains d'origine tubulaire proximale. La culture in vitro de cellules epitheliales de reins humains d'origine nephronique bien definie pourrait s'averer utile dans de nombreuses etudes definissant les facteurs et les mecanismes responsables des maladies et de reglements du rein. Dans cette etude, nous avons teste l'hypothese selon laquelle l'emploi d'un milieu de croissance sans serum permet la culture selective de cellules epitheliales de rein humain. Il est demontre que le cortex renal humain explante dans un milieu de croissance sans serum, bien defini au point de vue hormonal, donne naissance a une culture primaire de cellules epitheliales renales de morphologie homogene, capable de former des hemicystes. Bien que ces cellules soient capables de proliferer jusqu'a confluence en culture a partir d'explants, elles sont incapables de subir une culture secondaire stable. Une manipulation ulterieure de la surface du recipient de culture (une couche initiale de collagene bovin de type I suivi par l'absorption de macromolecules provenant de serum de veau foetal) a permis des cultures capables d'etre cultivees de facon secondaire avec une croissance d'au moins 30 generations cellulaires. Ces cellules ont ete identifiees comme etant d'origine tubulaire proximale, en utilisant un examen enzymatique histochimique, immunohistochimique, et ultrastructural.
- Published
- 1984
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