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In addition to two known staphylococcal enterotoxin-like genes (selj and selr), two novel genes coding for two superantigens, staphylococcal enterotoxins S and T (SES and SET), were identified in plasmid pF5, which is harbored by food poisoning-related Staphylococcus aureus strain Fukuoka 5. This strain was implicated in a food poisoning incident in Fukuoka City, Japan, in 1997. Recombinant SES (rSES) specifically stimulated human T cells in a T-cell receptor V␤9-and V␤16-specific manner in the presence of major histocompatibility complex (MHC) class II ؉ antigen-presenting cells (APC). rSET also stimulated T cells in the presence of MHC class II ؉ APC, although its V␤ skewing was not found in reactive T cells. Subsequently, we examined the emetic activity of SES and SET. We also studied SElR to determine emetic activity in primates. This toxin was identified in previous studies but was not examined in terms of possession of emetic activity for primates. rSES induced emetic reactions in two of four monkeys at a dose of 100 g/kg within 5 h of intragastric administration. In one monkey, rSET induced a delayed reaction (24 h postadministration) at a dose of 100 g/kg, and in the other one, the reaction occurred 5 days postadministration. rSElR induced a reaction in two of six animals within 5 h at 100 g/kg. On this basis, we speculate that the causative toxins of vomiting in the Fukuoka case are SES and SER. Additionally, SES, SER, and SET also induced emesis in house musk shrews as in the monkeys.Staphylococcus aureus produces a variety of superantigenic toxins (SAGTs), which selectively activate a vast number of T cells, depending on V␤ elements in the ␤ chain of a T-cell receptor (TCR), in direct association with major histocompatibility complex (MHC) class II molecules on antigen-presenting cells (APC) (14, 31). Staphylococcal SAGTs can be divided into three large groups and one minor group on the basis of similarity of amino acid sequences (31). Most toxins of the three groups, including staphylococcal enterotoxins A and B (SEA and SEB), exhibit strong emetic activity in primates (4, 16, 25); toxic shock syndrome toxin-1, grouped as the minor group, does not possess emetic activity in primates (14, 31). It is noteworthy that toxins designated SE-like toxins, such as SElP and SElR, which either have not been examined for emetic activity or have been reported not to have emetic activity, have been discovered in S. aureus strains (12,13,20,27). S. aureus strain Fukuoka 5 was isolated from food as the causative microbe in a food poisoning outbreak in Fukuoka City, Japan, in 1997, although this strain did not carry any well-recognized SAGT genes with emetic activity (19). Subsequently, Omoe et al. (19) discovered, using a plaque hybridization with a seg probe, that 2.8 kbp of the EcoRI fragment of plasmid pF5, carried by Fukuoka 5, carries two genes, a novel SAGT gene designated selr and a previously reported gene, selj (33).We undertook research to explore, using a PCR walking technique, whether there were addition...

Small molecules designed to mimic the binding of Smac protein to X-linked inhibitor of apoptosis protein (XIAP) are being pursued as a promising new class of anticancer drugs. Herein, we report the design, synthesis, and comprehensive structure-activity relationship studies of a series of conformationally constrained bicyclic Smac mimetics. Our studies led to the discovery of a number of highly potent and cell-permeable Smac mimetics and yielded important new insights into their structure-activity relationship for their binding to XIAP and for their activity in inhibition of cancer cell growth. Determination of the crystal structure of one potent Smac mimetic, compound 21, in complex with XIAP BIR3 provides the structural basis for its high-affinity binding to XIAP and for the design of highly potent Smac mimetics.

Objective To develop an Radiation Therapy Oncology Group (RTOG) atlas delineating gross tumor volume (GTV), and clinical target volume (CTV) to be used for preoperative radiotherapy of primary extremity soft tissue sarcoma (STS). Methods A consensus meeting was held during the RTOG meeting in January 2010 to reach agreement about GTV and CTV delineation on CT images for preoperative radiotherapy of high-grade large extremity STS. Data were presented to address the local extension of STS. Extensive discussion ensued to develop optimal criteria for GTV and CTV delineation on CT images. Results A consensus was reached on appropriate CT-based GTV and CTV. GTV is gross tumor defined by T1 contrast-enhanced MRI images. Fusion of MRI and CT is recommended to delineate the GTV. CTV for high-grade large STS typically includes GTV plus 3 cm margins in the longitudinal directions. If this causes the field to extend beyond the compartment, the field can be shortened to include the end of a compartment. The radial margin from the lesion should be 1.5 cm including any portion of the tumor not confined by an intact fascial barrier, bone or skin surface. Conclusion The consensus on GTV and CTV for preoperative radiotherapy of high-grade large extremity STS is available as web-based images as well as descriptive format through the RTOG. This is expected to improve target volume consistency and allow for rigorous evaluation of the benefits and risks of such treatment.

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