Publications

Our aim was to test the hypothesis that the vinca alkaloid vincristine could prevent doxorubicin-induced cardiomyocyte death and to identify the mechanisms involved. Adult mouse cardiac myocytes were incubated for 24 h with doxorubicin, with and without concurrent vincristine. Trypan blue exclusion showed that 50-60% of myocytes treated with doxorubicin alone survived. Concurrent vincristine treatment increased survival to 85%. Treatment with doxorubicin+vincristine activated the prosurvival signal Akt and diminished cytochrome C release. The PI3K/Akt inhibitor LY294002 and the MEK/ERK inhibitor PD98059 augmented doxorubicin cardiotoxicity and attenuated salvage during concurrent vincristine treatment, indicating that the mechanism of vincristine cardioprotection involves activation of specific survival signals. Vincristine retarded the onset of apoptosis in association with a delay in poly(ADP) ribose polymerase activation. Vincristine also exhibited greater protection than the antioxidant MPG. These novel findings may have clinical implications for the prevention of doxorubicin cardiomyopathy.

OBJECTIVE

The occurrence of intraoperative air leaks is an unavoidable complication during pulmonary surgeries. However, current surgical methods are generally ineffective in closing these visceral pleural defects, resulting in a decreased quality of life for patients. Here, we examined novel tissue engineered cell sheets for the closure of pleural defects in a porcine model.

METHODS

Skin biopsies were harvested from juvenile swine and tissue sheets composed of dermal fibroblasts were created using ex vivo culture on temperature-responsive dishes. After creating a visceral pleural injury model, the tissue engineered autologous dermal fibroblast sheets were transplanted directly to the defects without the use of sutures or additional adhesive agents, such as fibrin glue.

RESULTS

The tissue engineered autologous dermal fibroblast sheets attached directly to the lung surface providing an immediate seal against up to 25 cm H2O of airway pressure. Four weeks after transplantation, the dermal fibroblast sheets remained present on the pleural surface, providing permanent closure. The dermal fibroblast sheets were also responsive to changes in lung volume due to mechanical ventilation. No recurrences of air leaks were observed throughout the follow-up period.

CONCLUSIONS

This study presents the development of an effective sealant for visceral pleural defects using autologous cells that have the flexibility to respond to expansion and contraction during respiration.

BACKGROUND

In the Raloxifene Use for The Heart trial, 10 101 postmenopausal women with coronary heart disease (CHD) or multiple CHD risk factors were randomly assigned to 60 mg/d raloxifene or to placebo and followed for a median of 5.6 years. Raloxifene, a selective estrogen receptor modulator, was found to reduce the risk of invasive breast cancer and vertebral fractures but not the risk of cardiovascular events. Here, we provide further details about breast cancer incidence by tumor characteristics, duration of treatment, and subgroup.

METHODS

Reported breast cancer was adjudicated by an independent committee based on medical records and pathology reports. The primary analyses used Cox proportional hazards models with time to first breast cancer as the outcome. Subgroup effects were analyzed using similar models with terms for treatment by subgroup. All statistical tests were two-sided.

RESULTS

As previously reported, raloxifene reduced the incidence of invasive breast cancer by 44% (hazard ratio [HR] = 0.56; 95% confidence interval [CI] = 0.38 to 0.83; absolute risk reduction = 1.2 invasive breast cancers per 1000 women treated for 1 year). The lower incidence of invasive breast cancer reflected a 55% lower incidence of invasive estrogen receptor (ER)-positive tumors (HR = 0.45; 95% CI = 0.28 to 0.72). However, raloxifene treatment did not reduce the incidence of noninvasive breast cancer or of invasive ER-negative breast cancer. The reduced incidence of invasive breast cancer was similar across subgroups, including those defined by age, body mass index, family history of breast cancer, prior use of postmenopausal hormones, and 5-year estimated risk of invasive breast cancer.

CONCLUSION

Raloxifene reduces risk of invasive ER-positive breast cancer regardless of a woman's baseline breast cancer risk but does not reduce risk of noninvasive or ER-negative breast cancers. These results confirm those of the Multiple Outcomes of Raloxifene Evaluation, a previous randomized trial among women with osteoporosis.