Specific sequences of fibronectin activate the protein kinase C signal transduction pathway in invasive bladder cancer.

The mechanism of human bladder cancer cell invasion is not clear, but it appears that extracellular matrix components, such as fibronectin, may be involved. To investigate the role of fibronectin in tumor cell invasion and progression, we used an in vitro invasion assay to define the motility stimulating fragment of fibronectin for invasive human bladder cancer T24 cells. Using a modified Boyden chamber assay and purified fragments of fibronectin, we demonstrated that both the 120 kDa chymotrypsin generated fragment of fibronectin (containing the cell attachment RGD motif and additional sequences towards the carboxyl-terminal heparin binding domain), as well as the trypsin generated 60 kDa fragment of fibronectin (containing the carboxyl-terminal heparin binding domain and additional sequences towards the cell attachment RGD motif), were able to stimulate the migration of invasive human bladder cancer T24 cells. Control fragments containing only the amino-terminal gelatin binding region of fibronectin did not stimulate the motility of the human bladder cancer T24 cells. To determine the molecular mechanism in which these fragments may stimulate the migration of the T24 cells, we assayed for intracellular signal transduction pathway protein kinase C (PKC). We demonstrated that both the 120 kDa and the 60 kDa fragments were able to stimulate the activation of protein kinase C. Non-motility stimulating fragments of fibronectin were not able to activate protein kinase C. We conclude that the PKC signal transduction pathway may be involved in matrix mediated motility, and suggest that the inhibition of such pathway(s) may alter the malignant phenotype of human bladder cancer.

Bacillus Calmette-Guérin interacts with the carboxyl-terminal heparin binding domain of fibronectin: implications for BCG-mediated antitumor activity.

Intravesical bacillus Calmette-Guérin (BCG) has been shown to be an effective treatment for superficial transitional cell carcinoma of the bladder. The mechanisms by which BCG achieves this effect remain unclear. Reports have attributed an important role to fibronectin both in the initial attachment of BCG to bladder surfaces and in the limitation of tumor cell motility. In the present study, using limited protease cathepsin B degradation followed by Western blot analyses with antibodies to various domains of the fibronectin molecule, we showed that BCG appears to bind to fibronectin near the carboxyl terminal and adjacent to the heparin binding domain. Furthermore a 51-chromium release assay with human bladder cancer cell line T24 as target cells and lymphokine activated killer (LAK) cells as effector cells showed that fibronectin was needed for tumor cytotoxicity by the LAK cells. By using antibodies and peptides to various domains of the fibronectin molecule, the heparin binding domain, but not the cell binding domain, carboxyl terminal region, or the amino terminal region of the fibronectin molecule, was identified as essential to tumor cell lysis by the LAK cells. Flow cytometric analysis showed that both peripheral blood lymphocytes and the LAK cells express fibronectin receptors VLA-3, VLA-4 and VLA-5 on their surfaces. However, the numbers of receptors are not significantly different in the two cell populations. We conclude that, by binding near the carboxyl terminal region and adjacent to the heparin-binding domain of the fibronectin molecule, BCG may protect this region of the molecule from tumor proteases, and may thus allow the antitumor activity of the host immune cells to take place.

A reassessment of the shift from the classical theory of concepts to prototype theory.

A standard view within psychology is that there have been two important shifts in the study of concepts and that each has led to some improvements. The first shift was from the classical theory of concepts to probabilistic theories, the most popular of which is prototype theory. The second shift was from probabilistic theories to theory-based theories. In this article, I take exception with the view that the first shift has led to any kind of advance. I argue that the main reasons given for preferring prototype theory over the classical theory are flawed and that prototype theory suffers some of the same problems that have been thought to challenge the classical theory.

Changing disease patterns, changing values: problems of geriatric care in the U.S.A.: an outsider's view.

Changing disease patterns coupled with recent shift in societal values bring into focus, among other challenges, the problems of geriatric care, with their medical and social aspects. Medicare and Medicaid were meant to respond to the needs of geriatric care. However there is almost a general consensus that in spite of being valuable in many respects, Medicare and Medicaid have failed to generate considerable change in the overall care for the elderly. The basic characteristics of the American Health care system are not conducive to an approach which envisages geriatric care as a comprehensive primary care level, within a system of health care, combining medical with social activities in a team led by a competent physician. Since such an approach seems to be a most appropriate one, an attitude on the part of the medical profession which concentrates on the medical aspects only and neglects the entire complex of problems, substantial and organizational, associated with geriatric care, may lack utility. The problems the U.S. faces in the health field, geriatric care included, are common for today's industrialized societies. However, certain specific difficulties seems to result from the fact that some components of the health care system insist on solving problems generated by changing disease patterns and changing societal values, with no change in their own structure and their own value system.

Health care in a changing society: the health services of Israel.

In the pre-State era, Israeli society displayed an "ascetic" orientation with emphasis on austerity and egalitarianism. The medical profession was influenced by the basic philosophy of the country and coped successfully with the country's health problems, mainly by lowering morbidity and mortality rates. With the emergence of the State of Israel, mass immigration of people with different backgrounds, cultures, and values occurred, and health problems of the disability, dissatisfaction, and discomfort type arose. The existing medical organizations were unable to handle them. The story of three such organizations is detailed in brief: the first medical school in Jerusalem, the greatest supplier of curative services--the workers' sick fund (Kupa Holim), and the Ministry of Health. Their impact on the health services of the country is described. These services are splintered into numerous self-contained authorities and an understanding of the overall needs is lacking. This state of affairs reflects the antagonistic interests of the political powers behind the various health agencies. A concensus within the health field on the nature of the problems and their solution could be reached if the health organizations accepted a broader philosophy of health, comprising its somatic, mental, and social aspects, and if they commit themselves to applying this philosophy in their activities. This may lead to considerable changes in medical education, more attention being focused on the social functions of medicine than on medical technology; health care would become more comprehensive and would cover all aspects of health in its preventive, curative, and rehabilitative stages. Failure to meet the health needs of the changing society will constitute a false reading of the public pulse. Of late, the voices demanding the conquest of social diseases and the attainment of health in its broadest sense are becoming more and more audible.