Next Generation Nuclear Plant Phenomena Identification and Ranking Tables (PIRTs) Volume 5: Graphite PIRTs

Here we report the outcome of the application of the Nuclear Regulatory Commission (NRC) Phenomena Identification and Ranking Table (PIRT) process to the issue of nuclear-grade graphite for the moderator and structural components of a next generation nuclear plant (NGNP), considering both routine (normal operation) and postulated accident conditions for the NGNP. The NGNP is assumed to be a modular high-temperature gas-cooled reactor (HTGR), either a gas-turbine modular helium reactor (GTMHR) version [a prismatic-core modular reactor (PMR)] or a pebble-bed modular reactor (PBMR) version [a pebble bed reactor (PBR)] design, with either a direct- or indirect-cycle gas turbine (Brayton cycle) system for electric power production, and an indirect-cycle component for hydrogen production. NGNP design options with a high-pressure steam generator (Rankine cycle) in the primary loop are not considered in this PIRT. This graphite PIRT was conducted in parallel with four other NRC PIRT activities, taking advantage of the relationships and overlaps in subject matter. The graphite PIRT panel identified numerous phenomena, five of which were ranked high importance-low knowledge. A further nine were ranked with high importance and medium knowledge rank. Two phenomena were ranked with medium importance and low knowledge, and a further 14 were ranked medium importance and medium knowledge rank. The last 12 phenomena were ranked with low importance and high knowledge rank (or similar combinations suggesting they have low priority). The ranking/scoring rationale for the reported graphite phenomena is discussed. Much has been learned about the behavior of graphite in reactor environments in the 60-plus years since the first graphite rectors went into service. The extensive list of references in the Bibliography is plainly testament to this fact. Our current knowledge base is well developed. Although data are lacking for the specific grades being considered for Generation IV (Gen IV) concepts, such as the NGNP, it is fully expected that the behavior of these graphites will conform to the recognized trends for near isotropic nuclear graphite. Thus, much of the data needed is confirmatory in nature. Theories that can explain graphite behavior have been postulated and, in many cases, shown to represent experimental data well. However, these theories need to be tested against data for the new graphites and extended to higher neutron doses and temperatures pertinent to the new Gen IV reactor concepts. It is anticipated that current and planned future graphite irradiation experiments will provide the data needed to validate many of the currently accepted models, as well as providing the needed data for design confirmation

Delivery of sTRAIL variants by MSCs in combination with cytotoxic drug treatment leads to p53-independent enhanced antitumor effects

Mesenchymal stem cells (MSCs) are able to infiltrate tumor tissues and thereby effectively deliver gene therapeutic payloads. Here, we engineered murine MSCs (mMSCs) to express a secreted form of the TNF-related apoptosis-inducing ligand (TRAIL), which is a potent inducer of apoptosis in tumor cells, and tested these MSCs, termed MSC.sTRAIL, in combination with conventional chemotherapeutic drug treatment in colon cancer models. When we pretreated human colorectal cancer HCT116 cells with low doses of 5-fluorouracil (5-FU) and added MSC.sTRAIL, we found significantly increased apoptosis as compared with single-agent treatment. Moreover, HCT116 xenografts, which were cotreated with 5-FU and systemically delivered MSC.sTRAIL, went into remission. Noteworthy, this effect was protein 53 (p53) independent and was mediated by TRAIL-receptor 2 (TRAIL-R2) upregulation, demonstrating the applicability of this approach in p53-defective tumors. Consequently, when we generated MSCs that secreted TRAIL-R2-specific variants of soluble TRAIL (sTRAIL), we found that such engineered MSCs, labeled MSC.sTRAIL DR5, had enhanced antitumor activity in combination with 5-FU when compared with MSC.sTRAIL. In contrast, TRAIL-resistant pancreatic carcinoma PancTu1 cells responded better to MSC.sTRAIL DR4 when the antiapoptotic protein XIAP (X-linked inhibitor of apoptosis protein) was silenced concomitantly. Taken together, our results demonstrate that TRAIL-receptor selective variants can potentially enhance the therapeutic efficacy of MSC-delivered TRAIL as part of individualized and tumor-specific combination treatments. © 2013 Macmillan Publishers Limited All rights reserved