p53 promotes apoptosis in response to death stimuli by transactivation of target genes and by transcriptionindependent mechanisms. We recently showed that wild-type p53 rapidly translocates to mitochondria in response to multiple death stimuli in cultured cells. Mitochondrial p53 physically interacts with antiapoptotic Bcl proteins, induces Bak oligomerization, permeabilizes mitochondrial membranes, and rapidly induces cytochrome c release. Here we characterize the mitochondrial p53 response in vivo. Mice were subjected to ␥ irradiation or intravenous etoposide administration, followed by cell fractionation and immunofluorescence studies of various organs. Mitochondrial p53 accumulation occurred in radiosensitive organs like thymus, spleen, testis, and brain but not in liver and kidney. Of note, mitochondrial p53 translocation was rapid (detectable at 30 min in thymus and spleen) and triggered an early wave of marked caspase 3 activation and apoptosis. This caspase 3-mediated apoptosis was entirely p53 dependent, as shown by p53 null mice, and preceded p53 target gene activation. The transcriptional p53 program had a longer lag phase than the rapid mitochondrial p53 program. In thymus, the earliest apoptotic target gene products PUMA, Noxa, and Bax appeared at 2, 4, and 8 h, respectively, while Bid, Killer/DR5, and p53DinP1 remained uninduced even after 20 h. Target gene induction then led to further increase in active caspase 3. Similar biphasic kinetics was seen in cultured human cells. Our results suggest that in sensitive organs mitochondrial p53 accumulation in vivo occurs soon after a death stimulus, triggering a rapid first wave of apoptosis that is transcription independent and may precede a second slower wave that is transcription dependent.

Sphingosine 1‐phosphate (S1P), produced by two sphingosine kinase isoenzymes (SphK1 and SphK2), regulates many cellular processes important for breast cancer progression by binding to specific S1P receptors. SphK1 is overexpressed in breast cancer, and both estradiol (E2) and epidermal growth factor (EGF) activate SphK1. In this study, we examined how intracellularly produced S1P is secreted from breast cancer cells. Overexpression of SphK1, but not SphK2, increased S1P export from MCF7 cells, and downregulation of expression of SphK1, but not SphK2, decreased its export. Although both E2 and EGF activated SphK1 and increased intracellular S1P, only E2 significantly stimulated S1P secretion. Export of S1P was inhibited by MK571, an inhibitor of ABCC1 (multi‐drug resistant protein 1), and fumitrimorgin C, an inhibitor of ABCG2 (breast cancer resistance protein), but not by the ABCB1 inhibitor, verapamil. In addition, E2‐induced secretion of S1P was blunted by downregulation of ABCC1 or ABCG2. These findings suggest that E2‐induced export of S1P is mediated by specific ABC transporters and may play an important role in multidrug resistance in breast cancer. This work was supported by NIH grants R37 GM043880 and R01CA61774 to SS and 5K12HD055881 to KT.

The sphingolipid metabolite, sphingosine-1-phosphate (S1P), has emerged as a critical player in a number of fundamental biological processes and is important in cancer, angiogenesis, wound healing, cardiovascular function, atherosclerosis, immunity and asthma, among others. Activation of sphingosine kinases, enzymes that catalyze the phosphorylation of sphingosine to S1P, by a variety of agonists, including growth factors, cytokines, hormones, and antigen, increases intracellular S1P. Many of the biological effects of S1P are mediated by its binding to five specific G protein-coupled receptors located on the cell surface in an autocrine and/or paracrine manner. Therefore, understanding the mechanism by which intracellularly generated S1P is released out of cells is both interesting and important. In this review, we will discuss how S1P is formed and released. We will focus particularly on the current knowledge of how the S1P gradient between tissues and blood is maintained, and the role of ABC transporters in S1P release.

Anastomotic complications are responsible for significant morbidity and mortality following esophagectomy for cancer. Conflicting reports exist regarding the superiority of hand-sewn versus stapled techniques. This systematic review identified eight randomized clinical trials examining this issue. None of the studies reported significant differences in leak rate or early mortality. One study demonstrated a difference in stricture rates, with fewer for hand-sewn anastomoses. There is insufficient evidence to recommend one anastomotic technique over the other.

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Attention to identification of infants at risk and programs such as lactation counseling and universal screening for bilirubin (with appropriate interpretation) prior to discharge could have reduced the necessity for readmission regardless of the newborn length of stay.

Fluconazole prophylaxis is effective and safe in reducing IC and Candida colonization in premature infants, and has no impact on resistance.

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