Publications

While tissue engineering has long been thought to possess enormous potential, conventional applications using biodegradable scaffolds have limited the field's progress, demonstrating a need for new methods. We have previously developed cell sheet engineering using temperature-responsive culture dishes in order to avoid traditional tissue engineering approaches, and their related shortcomings. Using temperature-responsive dishes, cultured cells can be harvested as intact sheets by simple temperature changes, thereby avoiding the use of proteolytic enzymes. Cell sheet engineering therefore allows for tissue regeneration by either direct transplantation of cell sheets to host tissues or the creation of three-dimensional structures via the layering of individual cell sheets. By avoiding the use of any additional materials such as carrier substrates or scaffolds, the complications associated with traditional tissue engineering approaches such as host inflammatory responses to implanted polymer materials, can be avoided. Cell sheet engineering thus presents several significant advantages and can overcome many of the problems that have previously restricted tissue engineering with biodegradable scaffolds.

BACKGROUND

The accuracy of a woman's perception of her risk of developing breast cancer has gained importance as more options for primary prevention have become available for those at increased risk. Conversely, women at average risk who perceive themselves as at increased risk may suffer from avoidable anxiety or unnecessary treatment. This study examined characteristics associated with perception of breast cancer risk among women at average and increased risk.

METHODS

We included 1700 women 40-74 years old without a history of breast cancer. The outcome variable was a woman's perceived lifetime risk of developing breast cancer. The Gail model was used to categorize a woman's actual risk as average or high. Multivariate logistic regression models were used to model a woman's perception that her risk was (1) higher than average for those whose Gail score indicated average risk (<1.67% 5-year risk) and (2) accurate for those whose Gail score indicated increased risk (> or = 1.67% 5-year risk).

RESULTS

Of women at average risk, 72%, but only 43% of those at high risk, accurately perceived their risk. Among women at average risk, those who were younger, had a family history of breast cancer, had no history of childbirth, or had more frequent exposure to lay media information about breast health were more likely than women without these characteristics to overestimate their future risk. Among women at increased risk, younger women and those with a family history of breast cancer were more likely than women without these characteristics to accurately perceive their increased risk. African American women were less likely than white women to accurately perceive their risk.

CONCLUSIONS

A majority of women at high risk of developing breast cancer underestimate their risk, and a substantial proportion of women at average risk perceive they are at increased risk.

Matrix metalloproteinase-2 (MMP-2) plays an essential role in angiogenesis and arteriogenesis, two processes critical to restoration of tissue perfusion after ischemia. MMP-2 expression is increased in tissue ischemia, but the responsible mechanisms remain unknown. We studied the transcriptional activation of the MMP-2 gene in a model of hindlimb ischemia by using various MMP-2-lacZ reporter mice and chromatin immunoprecipitation. MMP-2 activity and mRNA were increased after hindlimb ischemia. Mice with targeted deletion of MMP-2 had impaired restoration of perfusion and a high incidence of limb gangrene, indicating that MMP-2 plays a critical role in ischemia-induced revascularization. Ischemia induced the expression and binding of c-Fos, c-Jun, JunB, FosB, and Fra2 to a noncanonical activating protein-1 (AP-1) site present in the MMP-2 promoter and decreased binding of the transcriptional repressor JunD. Ischemia also activated the expression and binding of p53 to an adjacent enhancer site (RE-1) and increased expression and binding of nuclear factor of activated T-cells-c2 to consensus sequences within the first intron. Deletion of either the 5' AP-1/RE-1 region of the promoter or substitution of the first intron abolished ischemia-induced MMP-2 transcription in vivo. Thus, AP-1 transcription factors and intronic activation by nuclear factor of activated T-cells-c2 act in concert to drive ischemia-induced MMP-2 transcription. These findings define a critical role for MMP-2 in ischemia-induced revascularization and identify both previously uncharacterized regulatory elements within the MMP-2 gene and the cognate transcription factors required for MMP-2 activation in vivo after tissue ischemia.