Reduction in surface urokinase receptor forces malignant cells into a protracted state of dormancy

Considerable evidence links urokinase plasminogen activator (uPA) bound to its surface receptor (uPAR) with enhanced invasiveness of cancer cells. By blocking uPAR expression in human epidermoid carcinoma cells (HEp3), we have now identified an additional and novel in vivo function for this receptor by showing that receptor-deficient cells enter a state of dormancy reminiscent of that observed in human cancer metastasis. Its main characteristic is survival without signs of progressive growth. Five clones transfected with a vector expressing uPAR antisense RNA under the beta-actin promoter were isolated and shown to have uPAR (at the mRNA and protein levels) reduced by 50 to 80%; four clones, transfected with vector alone and having uPAR levels similar to those of parental cells, served as controls. In confirmation of our previous results, reduced uPAR always coincided with a significantly reduced invasiveness. Each of the control clones produced rapidly growing, highly metastatic tumors within 2 wk of inoculation on chorioallantoic membranes (CAMs) of chick embryos. In contrast, each of the clones with low surface uPAR, whose proliferation rate in culture was indistinguishable from controls, remained dormant for up to 5 mo when inoculated on CAMs. Thus, the reduction in uPAR altered the phenotype of HEp3 tumor cells from tumorigenic to dormant. Although protracted, tumor dormancy was not permanent since in spite of maintaining low uPAR levels, each of the in vivo-passaged antisense clones eventually reemerged from dormancy to initiate progressive growth and to form metastases at a level of 20 to 90% of that of fully malignant control. This observation suggested that other factors, whose expression is dependent on cumulative and prolonged in vivo effects, can compensate for the lack of a full complement of surface uPAR required for the expression of malignant properties. These "reemerged," uPAR-deficient clones were easily distinguishable from the vector-transfected controls by the fact that after only 1 wk in culture, the invasion of CAM by all five clones and tumorigenicity of four of the five clones were reduced back to the values observed before in vivo maintenance. In contrast, dissociated and in vitro-grown cells of control tumors were fully invasive and produced large, metastatic tumors when reinoculated on CAMs. Quantitation of the percent of apoptotic and S-phase cells in vivo, in the control and uPAR-deficient, dormant clones, showed that the mechanism responsible for the dormancy was a diminished proliferation.     

Competitive forces and academic plastic surgery

Economic constraints developing as a result of rising health care costs in the United States pose significant challenges for and threats to the survival of academic plastic surgery. Declining clinical revenues, competition for patients and resources from other health care providers, and reductions in support of its education and research efforts necessitate a paradigm shift if it is to survive. Questionnaires were used to collect data from 92 of the 100 postgraduate training program directors of plastic surgery in the United States. The most common source of clinical income on a national basis was indemnity insurance. Sources of clinical income varied by region. The majority of programs, 80 percent, report that at least 75 percent of the income support for faculty came from practice income. Financial support for ancillary and research personnel, in large part, came from this same source. Resident salaries and benefits came largely from other resources. Generally as population density within the metropolitan area in which a program was located increased, so too did the number of competing plastic surgeons, including graduates of the program and nonacademic cosmetic and hand surgeons. However, levels of competition for cosmetic surgery in smaller metropolitan areas of some regions seem to be similar to those reported by programs in larger communities. Plastic surgery programs in very competitive communities received significantly greater amounts of their income from indemnity insurance and self-paying patients than did programs in less competitive metropolitan areas. Internal competition from other surgical and nonsurgical specialists within the same institution is likewise keen. Virtually all respondents, 93 percent, report that their institutions provided patient care in a least one designated center of excellence in the following disciplines: hand, microsurgery, craniofacial, cleft lip and palate, burn, and cosmetic surgery. This study suggests that centers of excellence are more likely to be present in metropolitan areas with fewer competing surgeons than in areas with large numbers of competing surgeons. The data did not demonstrate that the presence of a center of excellence substantially affected the sources or levels of clinical income. To survive as an academic entity, program directors must correctly perceive and fulfill the needs and wants of its stakeholders, particularly with regard to quality of life issues.     

Coercive power and forces affecting conformity.

"In a laboratory experiment… Ss worked on a card sorting task under a supervisor who created various conditions of coercive power… . It was hypothesized that the supervisor's inductions would set up punishment forces and opposing resisting forces both of which would determine S's conformity… . It is concluded that punishment forces and resistance forces are independent determinants of conformity to coercive power." (PsycINFO Database Record (c) 2010 APA, all rights reserved)