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G B Hubbard

Publications and source records attributed to G B Hubbard.

At least 55 records · Page 3Linked to original sources
PubMed1997

Fate of allogeneic skin transplantations in a marsupial (Monodelphis domestica).

Previously we reported that the South American gray short-tailed opossum, Monodelphis domestica, had an MHC class-I locus similar to that of eutherian species. In addition to the detection of lymphocyte antigens by cytotoxic antisera, we concluded that this marsupial rejected allogeneic skin grafts, as would be expected of animals with MHC class-I polymorphism. However, this conclusion was based on a limited number of skin transplants that were assayed for only a short period. Here we report the results of 22 reciprocal skin grafts made between individuals of known genetic relationships. On the basis of gross inspection of the grafts and histologic examination, we found that the average time of the onset of graft rejection was about 19 days and that the average time for complete graft rejection was about 31 days. In general, it took longer for the onset of graft rejection among pairs of genetically related animals than among less related animals. These results indicate unequivocally that this marsupial species has a high degree of class-I polymorphism and rejects allogeneic skin transplants in a manner similar to but more slowly than eutherian mammals.

Animals↗
PubMed1996

Adenoviral-mediated thymidine kinase gene transfer into the primate brain followed by systemic ganciclovir: pathologic, radiologic, and molecular studies.

Transduction of experimental gliomas with the herpes simplex virus thymidine kinase gene (HSV-tk) using a replication-defective adenoviral vector (ADV/RSV-tk) confers sensitivity to ganciclovir (GCV) leading to tumor destruction and prolonged host survival in rodents. To determine treatment tolerance prior to clinical trials, we conducted toxicity studies in 6 adult baboons (Papio sp.). The animals received intracerebral injections of either a high dose of ADV/RSV-tk [1.5 x 10(9) plaque-forming units (pfu)] with or without GCV, or a low dose of ADV/RSV-tk (7.5 x 10(7) pfu) with GCV. The low dose corresponded to the anticipated therapeutic dose; the high dose was expected to be toxic. Magnetic resonance imaging (MRI) of the brain was obtained before treatment and at 3 and 6 weeks after treatment. Animals receiving the high-dose vector and GCV either died or became moribund and required euthanasia during the first 8 days of treatment. Necropsies revealed cavities of coagulative necrosis at the injection sites. Animals receiving only the high-dose vector were clinically normal; however, lesions were detected with MRI at the injection sites corresponding to cystic cavities at necropsy. Animals receiving the low-dose vector and GCV were clinically normal, exhibited small MRI abnormalities, and, although no gross lesions were present at necropsy, microscopic foci of necrosis were present. The vector sequence was detected by polymerase chain reaction (PCR) at the injection sites and in non-adjacent central nervous system tissue in all animals. Recombinant DNA sequence was detected outside of the nervous system in some animals, and persisted up to 6 weeks. The viral vector injections stimulated the production of neutralizing antibodies in the animals. No shedding of the vector was found in urine, feces, or serum 7 days after intracerebral injection. This study suggests that further investigations including clinical toxicity trials of this form of brain tumor therapy are warranted.

Adenoviruses, Human↗
PubMed1996

Protection of non-murine mammals against encephalomyocarditis virus using a genetically engineered Mengo virus.

Genetically engineered Mengo viruses with artificial deletions in the 5' noncoding poly(C) tracts are highly attenuated for pathogenicity when introduced as live vaccines into the natural murine host. Inoculation produces lifelong protective immunity without disease or viral persistence. This report extends the vaccination studies to non-murine hosts, including baboons, macaques and domestic pigs, all of which are susceptible to severe cardiovirus epizootics. All animals of these species that were inoculated with vMC24, an engineered strain of Mengo, seroconverted. When the immunized animals were challenged, they were protected against lethal doses of encephalomyocarditis virus (EMCV) derived from currently circulating epizootic strains. In baboons, the neutralizing antibody titers induced by vMC24 were significantly higher than from an inactivated EMCV vaccine. Moreover, terminal histopathology on baboons (inoculated intramuscularly), macaques (inoculated intracerebrally), and pigs (inoculated intramuscularly) showed few, if any, gross lesions characteristic of EMCV-like disease, in the vMC24 vaccinates. We suggest that genetically engineered, short poly(C) Mengo viruses may be universally potent attenuated vaccines for many types of animals and can possibly provide safe, efficacious protection against all cardioviruses of the EMCV serotype.

Animals↗
PubMed1995

Ultraviolet radiation-induced skin lesions in laboratory opossums (Monodelphis domestica) exposed from the weanling stage.

After repeated exposure to ultraviolet radiation, adult laboratory opossums (Monodelphis domestica) may develop hyperplasia and neoplasia of the shaved skin. We exposed opossums from the weanling stage (8-10 weeks after birth) and compared the incidence of lesions at designated time points with those observed following introduction of adults (around 5 months old) to the same irradiation protocol (125 J/m2 of UVB three times each week for up to 40 weeks). The overall incidence of hyperplasia and neoplasia among opossums exposed from the weanling stage was markedly lower than among animals first exposed as adults, and hyperkeratosis and sarcoma were not observed. Although freckling was widespread, cutaneous melanocytic nevi were rare among animals first exposed as weanlings; however, one animal without freckling developed malignant melanoma with presumptive metastasis to the spleen. The basis of the lowered lesion incidence among weanling-introduced animals is not clear; it may be that cutaneous immunity to ultraviolet radiation damage is more efficient in juveniles than in adults.

Age Factors↗
PubMed1995

Anti-tumor action of dietary restriction is lesion-dependent in male Fischer 344 rats.

The effects of dietary restriction (DR) on spontaneous oncogenesis in male Fischer 344 rats were analyzed. Previously reported analyses of studies carried out in our laboratory demonstrated that DR reduces the incidence and delays the onset, but not the progression, of leukemia in male F344 rats. In this report, the influence of DR on pituitary tumors, adrenal pheochromocytoma, pancreatic islet cell tumors, and interstitial cell tumors of the testis was analyzed. DR reduced the relative incidence (relative onset rates) and delayed the onset of the four tumors. DR also retarded the progression (duration from onset to death) of pituitary tumors and pheochromocytoma. DR has delayed the onset of all tumors of the male F344 rat so far analyzed, but its effect on tumor progression appears to be lesion-dependent.

Adenoma, Islet Cell↗
PubMed1995

Surgical correction of severe vaginal introital stenosis in female baboons (Papio sp.) infected with simian agent 8.

Simian agent 8 (SA8) is a neurotropic, endemic alphaherpesvirus in Papio sp. Lesions associated with simian agent 8 infections usually involve the genitalia of sexually mature baboons. In females, secondary bacterial infections may lead to scarring of the vulva and perineum, with resulting vaginal obstruction. Affected baboons are poor breeders and often develop urinary tract infections due to retention of urine in the vagina. Reconstructive vaginal surgery was performed on seven baboons with vaginal obstruction. Four weeks before surgery, 50 mg of Depo-Provera was administered intramuscularly to each animal to arrest the estrous cycle, reduce swelling, and allow adequate surgical exposure of the vagina. Ventral and circular incisions were made around the constricted vagina. The peripheral skin was excised to break down the underlying connective tissue, allowing access to the vaginal mucosa. Healthy vaginal tissue was then opposed to the incised skin edges with 3-0 Vicryl in an interrupted pattern. Once healed, the vaginas remained patent, allowing normal mating and urination. Nine months after surgery, five baboons had healthy infants, and pregnancy was confirmed in the other two animals. The described procedure may allow female baboons previously infertile and at risk of urinary tract infections to be returned to a healthy reproductive state.

Animals↗
PubMed1994

Malignant melanoma in ultraviolet irradiated laboratory opossums: initiation in suckling young, metastasis in adults, and xenograft behavior in nude mice.

Litters of suckling young of the laboratory opossum (Monodelphis domestica) were irradiated with UV light from sunlamps with a spectral emission peak at 302 nm (UVB) to induce melanocytic nevi. Total doses of 0.87-5.0 kJ/m2 were divided equally among up to 14 exposures during the 19 days from birth. Of 358 sucklings exposed, 217 survived to weaning, and 22 (10%) possessed a nevus when shaved and examined at or after weaning. Affected animals were then exposed 3 times/week to 125 J/m2 of UVB for up to 45 weeks to promote progression to malignancy. Nevi of 8 of the 20 chronically-exposed animals progressed to malignant melanoma with metastases to lymph node(s). Cell cultures were prepared from affected nodes to confirm that pigmented nodal cells were metastatic melanomas. One established cell line (TD15L) contained highly pigmented, dendritic, malignant melanoma cells. These cells, injected s.c. as xenogeneic grafts into athymic nude mice, remained viable in the subcutis and were moderately tumorigenic in the dermis. UVR exposure of Monodelphis sucklings is a novel, effective, and proficient way of initiating melanocytic lesions for studies on susceptibility and progression to melanoma, and the cell lines derived from these melanomas will provide promising new reagents for chemotherapy and immunotherapy investigations.

Animals↗
PubMed1994

Susceptibility to ultraviolet-induced corneal sarcomas is highly heritable in a laboratory opossum model.

The laboratory opossum, Monodelphis domestica, develops hyperplasia and neoplasia of the corneal stroma after repeated exposure to low doses of ultraviolet radiation (UVR) (non-erythemic in skin). We exposed adult animals from genetically diverse families within our colony to determine whether there are any heritable components to the risk of this form of eye cancer. From about 5 months of age, animals were exposed 3 times a week to a dose of about 125 J/m2 of UVB (spectral peak = 302 nm). Thirty-three sibships (151 individuals) completed at least 30 weeks of the protocol and 137 individuals completed 45 weeks. For genetic analysis, each animal was classified at 30 and 45 weeks as affected with corneal sarcoma or not. Heritabilities were estimated for the dichotomous eye-tumor trait which was highly heritable at both time points. This eye-cancer model system is valuable as a source of material for in vitro studies of angiogenesis and neoplastic transformation, for in vivo studies of tumor therapy and prevention, and for further research on the genetic determinants of cancer.

Animals↗
PubMed1994

Genetic analysis of ultraviolet radiation-induced skin hyperplasia and neoplasia in a laboratory marsupial model (Monodelphis domestica).

Monodelphis domestica, the laboratory opossum, develops hyperplasia and neoplasia of shaved skin after repeated exposure to ultraviolet radiation (UVR). We exposed Monodelphis from genetically diverse families within our colony to determine whether there are any heritable components to the risk of two distinct skin lesion phenotypes-melanocytic nevus (MN) and advanced hyperkeratosis (HK). From about 5 months of age, animals were shaved and exposed three times a week to a dose of about 125 J/m2 of UVR (spectral peak, 302 nm; range, 280-400 nm). Of 33 sibships (151 individuals) that completed at least 30 weeks of the protocol, 137 completed 45 weeks. For genetic analyses, each animal was classified at 30 and 45 weeks as affected with MN and HK or not affected. Heritabilities were estimated using a variance decomposition approach. Susceptibility to MN showed no significant evidence for a genetic component at 30 or 45 weeks. In sharp contrast, susceptibility to HK was under virtually complete genetic control (heritability, 0.999; P < 0.001) at 30 weeks, and had a moderately high heritability (0.702; P < 0.001) at 45 weeks. We conclude that this model has great potential for identifying genes that confer susceptibility to UVR-induced skin lesions and for investigating environmental factors that may contribute to the increasing incidence of skin cancer in human populations.

Animals↗
PubMed1993

Prolonged tamoxifen exposure selects a breast cancer cell clone that is stable in vitro and in vivo.

The effects of long-term tamoxifen exposure on cell growth and cell cycle kinetics were compared between oestrogen receptor (ER)-positive (MCF-7) and ER-negative (MDA-MB-231) cell lines. In the MCF-7 cell line, prolonged tamoxifen exposure (0.5 mumol/l for > 100 days) blocked cells in G0-G1 of the cell cycle, and slowed the doubling time of cells from 30 to 59 h. These effects corresponded to an increase in the cellular accumulation of tamoxifen over time [mean area under concentration curve (AUC) = 77.92 mumoles/10(6)/cells/day]. In contrast, in the MDA-MB-231 cell line, long-term tamoxifen exposure had no obvious effect on the doubling time, and reduced cellular tamoxifen accumulation (mean AUC = 50.50 mumoles/10(6)/cells/day) compared to the MCF-7 cells. Flow cytometric analysis of MDA-MB-231 cells demonstrated that a new tetraploid clone emerged following 56 days of tamoxifen exposure. Inoculation of the MDA-MB-231 tetraploid clone and MDA-MB-231 wildtype cells into the opposite flanks of athymic nude mice resulted in the rapid growth of tetraploid tumours. The tetraploid tumours maintained their ploidy following tamoxifen treatment for nine consecutive serial transplantations. Histological examination of the fifth transplant generation xenografts revealed that the tetraploid tumour had a 25-30 times greater mass, area of haemorrhage and necrosis, a slightly higher mitotic index and was more anaplastic than the control neoplasm. The control wildtype MDA-MB-231 tumours maintained a stable ploidy following tamoxifen treatment until the eighth and ninth transplantation, when a tetraploid population appeared, suggesting that tamoxifen treatment may select for this clone in vivo. These studies suggest that prolonged tamoxifen exposure may select for new, stable, fast growing cell clones in vitro as well as in vivo.

Animals↗
PubMed1993

Diet and the suitability of the male Fischer 344 rat as a model for aging research.

There has been concern about the suitability of the male Fischer 344 (F344) rat as a model for aging research because of the high prevalence of a single disease, severe nephropathy, at advanced ages which confounds the interpretation of an aging study. In a publication from our laboratory, Iwasaki et al. (1988) reported that replacing the casein in our standard semisynthetic diet with soy protein markedly decreases the progression of nephropathy with advancing age in ad libitum fed male F344 rats. In the present study, it is shown that replacing the casein with lactalbumin does not decrease the occurrence of severe nephropathy in ad libitum fed rats. It is also shown that dietary restriction (DR) studies can be effectively executed in the male F344 rat when soy protein is the source of dietary protein. It is further shown that when the energy intake of the rats fed soy protein-containing diets was reduced to 60% of the ad libitum intake, almost one-third of the rats died with an absence of severe morphologic lesions, that is, lesions which contribute to the death of the rat. It is concluded that the male F344 rat is an excellent model for aging research when soy protein is the source of dietary protein; no single disease process was found to be primarily responsible for death with such a diet.

Aging↗
PubMed1993

Spontaneously generated non-Hodgkin's lymphoma in twenty-seven simian T-cell leukemia virus type 1 antibody-positive baboons (Papio species).

Simian T-cell leukemia virus type 1 (STLV-1), a type C retrovirus associated with leukemia/lymphoma in Old World monkeys, is closely related to human T-cell leukemia virus type 1, the etiologic agent of adult T-cell leukemia/lymphoma in humans. In a colony of 3200 baboons, the prevalence of antibodies to STLV-1 is more than 40%. Seropositivity is more frequent in female baboons than in males and increases with age. Of 27 STLV-1 antibody-positive baboons with non-Hodgkin's lymphoma, 20 were females and 7 were males, ranging in age from 3 to 21 years (mean, 13 years). Non-Hodgkin's lymphoma was not found in STLV-1 antibody-negative baboons. Clinical signs and laboratory findings were variable but generally included lethargy, low body weights, anemia, dyspnea, lymphadenopathy, hepatosplenomegaly, pneumonia, nodular skin lesions, and leukemia with or without multilobulated lymphocytes in peripheral blood. Radiography revealed pulmonary infiltrates consistent with pneumonia in 17 of the baboons. Serum chemical values were normal except for hypercalcemia in one baboon. Lymphocytosis was found in 18 of the baboons, with leukemia diagnosed in 11. At necropsy, variable enlargement of lymph nodes and other lymphopoietic tissue was usually found. Pale tan to white space-occupying foci typical of proliferative lymphoid tissue were often found in various organs, including lungs, spleens, livers, skin, and hearts. The lungs in 14 baboons had thickened pleuras, congestion,edema, and large tan to brown areas of consolidation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Clinical parameters of the normal baboons (Papio species) and chimpanzees (Pan troglodytes).

Improved equipment and advanced progressive techniques by scientists using baboons and chimpanzees in biomedical research have resulted in improved clinical laboratory data. The use of state-of-the-art clinical laboratory instruments, methodologies with improved accuracy, and an increased variety of individual tests routinely requested and performed has necessitated the comparison of current data with prior data produced in our laboratory and with those values reported in the literature. In addition to an expanded hematologic profile, including red blood cell distribution width and mean platelet volume, and a more comprehensive chemical profile of 28 individual tests, additional data collected included values for coagulation profiles, arterial blood gases, serum protein electrophoresis, and urine osmolalities. Samples for evaluation were obtained from clinically normal sedated adult baboons (Papio species) and chimpanzees (Pan troglodytes) and processed conventionally according to Good Laboratory Practice Act standards. Arithmetic means were calculated, values of 3 standard deviations or greater were eliminated, and means were recalculated to include 2 standard deviations. All data correlated well with prior in-house values, and no remarkable differences from established data were detected, thus indicating the reliability of past and present data. Data compared favorably with normal clinical values established for humans.

Animals↗
PubMed1992

Regional distribution of mammalian corneal aldehyde dehydrogenase and alcohol dehydrogenase.

The regional distribution of mouse aldehyde dehydrogenase (ALDH) and alcohol dehydrogenase activities in mouse ocular tissues was examined using spectrophotometric and agarose-isoelectric focusing techniques. The results established that these enzymes are predominantly localized in the cornea. Biochemical and histochemical analyses of the localization of these enzymes in the corneas of common domestic mammals (pigs, sheep, and cattle) and in baboons revealed species differences, with high levels being reported in corneal epithelium (pigs and baboons) and endothelium (sheep and cattle). The presence of these enzymes in the corneal epithelium is consistent with their proposed catalytic role in the detoxification of ultraviolet (UV)-induced peroxidic aldehydes, and with the proposed role for corneal ALDH in UVB absorption.

Alcohol Dehydrogenase↗