Using Atomic Force Microscopy to Predict Tumor Specificity of ICAM1 Antibody-Directed Nanomedicines.

Atomic force microscopy (AFM) is a powerful tool to detect in vitro antibody-antigen interactions. To date, however, AFM-measured antibody-antigen interactions have yet to be exploited to predict in vivo tumor specificity of antibody-directed nanomedicines. In this study, we have utilized AFM to directly measure the biomechanical interaction between live triple negative breast cancer (TNBC) cells and an antibody against ICAM1, a recently identified TNBC target. For the first time, we provide proof-of-principle evidence that in vitro TNBC cell-ICAM1 antibody binding force measured by AFM on live cells more precisely correlates with in vivo tumor accumulation and therapeutic efficacy of ICAM1 antibody-directed liposomes than ICAM1 gene and surface protein overexpression levels. These studies demonstrate that live cell-antibody binding force measurements may be used as a novel in vitro metric for predicting the in vivo tumor recognition of antibody-directed nanomedicines.

What's so important about conducting research involving third parties?

Controversy has arisen over the long-standing practice of collecting family health and behavioral history information in the course of conducting biomedical research. Identifiable individuals (third parties) on whom investigators collect private data through primary research subjects (probands) also are considered research subjects. At issue is whether informed consent is required from third parties prior to obtaining information about them from probands. A recent federal regulatory ruling dictates that investigators must either obtain informed consent from all third parties or their research must qualify for a waiver of consent. Because of the ruling, a traditional family medical history questionnaire, typical of those routinely used in genetic epidemiologic studies of familial risk, failed to meet the criteria for the waiver. The implications of this ruling are far-reaching. They could influence the quality of research in the United States on the causes of most human diseases. To enable continuing medical and bioethical education on the topic, in March 2001, Virginia Commonwealth University hosted a 2-day open conference, "Third Party Rights and Risks: A Forum on Informed Consent from Persons Affected by the Study of Human Subjects." International leaders from the fields of biomedical ethics and law convened with federal regulatory officials, Institutional Review Board members, academic and industry scientists, and patient-family rights advocates to discuss and debate this critical topic. Conference presenters submitted papers to clarify the issues, promote continued debate, and assist in the formulation of policy recommendations regarding third-party rights and risks.

Historical background of clinical trials involving women and minorities.

The author provides a historical context for the difficult ethical and clinical issues associated with the inclusion of women and members of minority groups in clinical research. He cites as a point of departure the Nuremberg Code of the late 1940s, which declared the fundamental dignity of human beings involved as research subjects, a principle that was quickly endorsed worldwide. From the period following World War II through the 1970s, the prevailing attitude--not always practiced--toward research subjects in the United States was that they should be protected from exploitation. That attitude was reflected in the first broad federal policy on research subjects, created in 1966. During those years, research was widely regarded by the public as dangerous and of little value to individual participants; it is remarkable that so many men and women consented to participate in clinical studies at that time. Furthermore, during the 1970s, for reasons explained by the author, various events--the abortion debate, disclosures from the infamous Tuskegee syphilis study, Nixon's "war on cancer," new federal regulations in 1974 and 1975 (the latter providing additional protection for pregnant women in research), the broad interpretation of the FDA's 1977 policy excluding pregnant or potentially pregnant women from clinical trials, and the tendency of blacks and persons from other minority groups to shun participation in research--tended to deter participation of women and members of minority groups in clinical research.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of chronic exposure to tobacco smoke on the antibacterial defenses of the lung.

To evaluate the effects of cigarette smoking on the host defenses of the lung, male CD rats were exposed to fresh whole smoke for up to 60 consecutive days. Intrapulmonary deposition of smoke and animal exposure levels, quantified with decachlorobiphenyl and other smoke tracers, indicated a daily cigarette exposure equivalent to approximately a pack and a half per day in man. Pulmonary alveolar macrophage function in situ was quantified by the inactivation of an aerosolized challenge of Staphylococcus aureus six hours after inoculation. Controls (n=120) inactivated 88.8+/-0.64% of the staphylococci. Exposure to whole smoke did not impair intrapulmonary antistaphylococcal defenses, with inactivation rates of 89.8+/-0.97% (n=49) and 89.1+/-0.46% (n=74) at 30 and 60 days, respectively. Inactivation distribution frequency analysis in controls revealed that 7% of animals had inactivation values greater than two standard deviations from the mean. With prolonged exposure mean with less skewing towards the abnormal. Alveolar macrophages harvested from smoked animals were comparable in viability and in vitro antistaphylococcal activity to controls, appeared to be metabolically activated and had specific stereologic ultrastructural alterations. These studies indicate that chronic exposure to tobacco smoke does not impair, and in fact may stimulate, the host defenses of the lung, as evaluated by in vivo and in vitro pulmonary alveolar macrophage function.

Depressant effect of marihuana smoke on antibactericidal activity of pulmonary alveolar macrophages.

Other than the potentially therapeutic bronchodilatory influences of marihuana, very little is known of its biologic effects on the lung. To evaluate this problem, alveolar macrophages were harvested from rats by bronchopulmonary lavage and incubated in vitro with Staphylococcus albus and marihuana smoke of standardized 2.2-percent tetrahydrocannabinol content in graded amounts. After three hours, control alveolar macrophages inactivated 78.0 +/- 5.0 percent of the staphylococcal challenge. There was a dose-dependent depression of alveolar macrophage bactericidal activity, with 66.7 +/- 7.1 percent, 23.7 +/- 7.0 percent, 20.5 +/- 7.0 percent, and 11.4 +/- 7.6 percent of the bacteria killed following exposures to 2 ml, 4 ml, 6 ml, or 8 ml of marihuana smoke, respectively. Differential filtration of marihuana smoke revealed that the alveolar macrophage cytotoxin was present in the gas phase of the smoke and was water-soluble. Studies on purified tetrahydrocannabinol and on tetrahydrocannoabinol-extracted marihuana revealed that the impairment in alveolar macrophage function was not related to the psychomimetic or bronchodilatory components of marihuana.