Interrelationship between protein phosphatase-2A and cytoskeletal architecture during the endothelial cell response to soluble products produced by human head and neck cancer.

Tumor neovascularization is necessary for the progressive development of all solid tumors, including head and neck squamous cell carcinomas (HNSCCs). The angiogenic process includes increased endothelial cell motility. Our prior studies have shown the importance of protein phosphatase-2A (PP-2A) in restricting endothelial cell motility. Because motility is regulated by the polymerization/depolymerization of the cellular cytoskeleton, the present study defined the interrelationship between PP-2A and the cytoskeleton during endothelial cell responses to HNSCC-derived angiogenic factors. PP-2A was shown to colocalize with microtubules of unstimulated endothelial cells. However, exposure to HNSCC-derived products resulted in a more diffuse distribution of PP-2A staining and a loss of filamentous tubulin. The feasibility of pharmacologically preventing this cytoskeletal disorganization as a means of blocking tumor-induced angiogenesis was tested. This was accomplished by use of 1alpha,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] and all-trans -retinoic acid to indirectly stimulate PP-2A activity through their capacity to elevated intracellular levels of the second messenger ceramide. Pretreatment of endothelial cells with either 1,25(OH)(2)D(3) or retinoic acid prevented the cytoskeletal disorganization that otherwise occurs in endothelial cells on exposure to HNSCC-derived products. These studies support the feasibility of using elevation of PP-2A to prevent the morphogenic component of the angiogenic process that is stimulated by HNSCC-derived factors.

Xenotransplantation: an overview of microbiological risks and potentials for risk management.

Xenotransplantation is the use of animal organs, tissues or cells for transplantion into humans to treat a variety of medical conditions. If proven efficacious, the technique could be used as one means of alleviating the disparity between the growing demand for transplantable organs, tissues and cells, and the availability of human-origin transplants world-wide. Just as the practicality and efficacy of the technology need to be investigated, so too does the potential for associated infectious disease risk. While much remains to be learned about the microbiological risk associated with xenotransplantation, the elements to be incorporated into xenotransplantation risk management schemes can be considered, using what is currently known about the infectious agents potentially relevant to the xenotransplantation setting.

Isolated lung perfusion with tumor necrosis factor: a swine model in preparation of human trials.

Isolated lung perfusion with tumor necrosis factor (TNF) potentially could deliver high doses of drug and avoid systemic toxicity in patients with unresectable lung cancer or metastases. We investigated the feasibility of isolated lung perfusion with TNF in a pig model. Eleven animals had left-sided isolated lung perfusion with no TNF (n = 3), 40 micrograms/kg TNF (n = 2), 80 micrograms/kg TNF (n = 3), and 40 micrograms/kg TNF at moderate (39.5 degrees C) hyperthermia (n = 3). Hemodynamic monitoring and measurement of systemic and pulmonary circuit TNF levels were performed. Surviving animals were electively sacrificed a minimum of 6 months after isolated lung perfusion. All sham-perfused pigs survived. Isolated lung perfusion elevated pulmonary artery pressure, decreased cardiac output, and had minimal effects on mean pressure (15 +/- 0 versus 32 +/- 8 mm Hg, 4.5 +/- 1.1 versus 3.03 +/- 0.03 L/min, 67 +/- 11 versus 61 +/- 2 mm Hg; before versus after 90 minutes of isolated lung perfusion). Both 40 micrograms/kg animals and 2 of the 3 hyperthermic perfusion pigs survived, with 1 requiring pneumonectomy. Of the three 80 micrograms/kg animals, 1 survived, 1 died, and 1 required pneumonectomy. Survivors, compared with dying animals, had lower systemic/pulmonary TNF ratios and lower peak systemic TNF levels. All surviving pigs were electively sacrificed. These data justify phase I human protocols of isolated lung perfusion with TNF and hyperthermia; however, intraoperative leak rates must be monitored to ensure pulmonary isolation because systemic TNF levels may dictate treatment morbidity/mortality.

The cat/feline immunodeficiency virus model for transmucosal transmission of AIDS: nonoxynol-9 contraceptive jelly blocks transmission by an infected cell inoculum.

OBJECTIVES: To develop an animal model to study transmucosal lentivirus transmission, and to determine whether topical application of contraceptive jelly can block transmission by an infected cell incoulum. DESIGN: Feline immunodeficiency virus (FIV), a lentivirus similar to HIV, causes an AIDS-like disease in domestic cats. HIV is transmitted primarily across mucosal surfaces, and infected cells may be important in this transmission. We tested the ability of FIV-infected cells to transmit infection across the vaginal, rectal and oral mucosa of the cat, and whether a vaginal contraceptive jelly could prevent such transmission. METHODS: An inoculum consisting of 2 million FIV-infected primary cat T cells was administered vaginally, rectally or orally to female cats that had received either no pretreatment or pretreatment with a contraceptive jelly containing the detergent nonoxynol-9 as spermicide. Transmission was detected by monitoring recipient animals for viral antibodies and by viral cultures of blood leukocytes. RESULTS: A single dose of the infected cell inoculum efficiently transmitted FIV infection when delivered into the vagina or rectum (10 out of 11 animals became infected). Pretreatment of the vagina (five animals) or rectum (four animals) with contraceptive jelly protected all animals from transmission by the highly infectious inoculum. CONCLUSIONS: The cat/FIV model provides an efficient means to study transmucosal transmission of lentivirus infections, and for assessing vaginal barrier methods that could block transmission. One such method, nonoxynol-9 contraceptive jelly, effectively prevents transmucosal transmission by an FIV-infected cell inoculum.

Epidemiologic observations on feline immunodeficiency virus and Toxoplasma gondii coinfection in cats in Baltimore, Md.

Five hundred eighty-five serum samples obtained between 1980 and 1981 from a diverse population of cats were tested by use of an indirect immunoperoxidase assay for antibodies to feline immunodeficiency virus (FIV). Results of 14 of the samples were positive (prevalence, 2.4%). The FIV-positive cats were markedly older than the overall population and frequently were coinfected (57%) with Toxoplasma gondii. The Toxoplasma titers of the FIV-positive cats were significantly (P less than 0.03) higher than those of the FIV-negative cats. The FIV-positive cats were not coinfected with FeLV. Our findings suggested that FIV-associated immunosuppression may be a factor in active Toxoplasma infection in adult cats.