Anti-tumor effects of retinoids combined with trastuzumab or tamoxifen in breast cancer cells: induction of apoptosis by retinoid/trastuzumab combinations

INTRODUCTION: HER2 and estrogen receptor (ER) are important in breast cancer and are therapeutic targets of trastuzumab (Herceptin) and tamoxifen, respectively. Retinoids inhibit breast cancer growth, and modulate signaling by HER2 and ER. We hypothesized that treatment with retinoids and simultaneous targeting of HER2 and/or ER may have enhanced anti-tumor effects. METHODS: The effects of retinoids combined with trastuzumab or tamoxifen were examined in two human breast cancer cell lines in culture, BT474 and SKBR3. Assays of proliferation, apoptosis, differentiation, cell cycle distribution, and receptor signaling were performed. RESULTS: In HER2-overexpressing/ER-positive BT474 cells, combining all-trans retinoic acid (atRA) with tamoxifen or trastuzumab synergistically inhibited cell growth, and altered cell differentiation and cell cycle. Only atRA/trastuzumab-containing combinations induced apoptosis. BT474 and HER2-overexpressing/ER-negative SKBR3 cells were treated with a panel of retinoids (atRA, 9-cis-retinoic acid, 13-cis-retinoic acid, or N-(4-hydroxyphenyl) retinamide (fenretinide) (4-HPR)) combined with trastuzumab. In BT474 cells, none of the single agents except 4-HPR induced apoptosis, but again combinations of each retinoid with trastuzumab did induce apoptosis. In contrast, the single retinoid agents did cause apoptosis in SKBR3 cells; this was only modestly enhanced by addition of trastuzumab. The retinoid drug combinations altered signaling by HER2 and ER. Retinoids were inactive in trastuzumab-resistant BT474 cells. CONCLUSIONS: Combining retinoids with trastuzumab maximally inhibits cell growth and induces apoptosis in trastuzumab-sensitive cells. Treatment with such combinations may have benefit for breast cancer patients

Intravenous Fluid Management Practices in Kidney Transplant Patients: A Multicenter Observational Cohort Pilot Study

Background: Limited evidence exists with regard to best practices in fluid management during kidney transplantation, which may directly affect the incidence of DGF. The authors of this study embarked on a collaborative observational multicenter pilot study to evaluate fluid administration practices in different transplant centers, with a focus on the relationship between total administered crystalloid volume and its association with DGF. Methods: Twenty consecutive kidney transplant patients were included from 9 academic medical centers in the United States. One hundred eighty patients were included in the final cohort and variables were compared between patients with and without DGF. Administered crystalloid volume was the primary variable of interest; however, additional patient and surgical variables were compared between patients with and without DGF. Variation in crystalloid administration was explored between centers by comparing median administered crystalloid volumes per kilogram of body weight. Also, unadjusted and adjusted logistic regression analyses were performed to determine which variables were independently associated with DGF. Results: Multivariable regression modeling demonstrated that cold ischemic time and ephedrine use during surgery were independently associated with DGF. There was no independent association between administered crystalloid volume and DGF. Conclusion: In this study of patients having kidney transplantation, we did not find an independent association between administered crystalloid volume and DGF, although there was significant variability in crystalloid administration between centers. Our data suggest that DGF was driven mainly by surgical factors such as cold ischemic time. Ephedrine was also independently associated with DGF, which should be explored in future studies

Pleiotropic role of TRAF7 in skull-base meningiomas and congenital heart disease

While somatic variants of TRAF7 (Tumor necrosis factor receptor-associated factor 7) underlie anterior skull-base meningiomas, here we report the inherited mutations of TRAF7 that cause congenital heart defects. We show that TRAF7 mutants operate in a dominant manner, inhibiting protein function via heterodimerization with wild-type protein. Further, the shared genetics of the two disparate pathologies can be traced to the common origin of forebrain meninges and cardiac outflow tract from the TRAF7-expressing neural crest. Somatic and inherited mutations disrupt TRAF7-IFT57 interactions leading to cilia degradation. TRAF7-mutant meningioma primary cultures lack cilia, and TRAF7 knockdown causes cardiac, craniofacial, and ciliary defects in Xenopus and zebrafish, suggesting a mechanistic convergence for TRAF7-driven meningiomas and developmental heart defects