Evidence for Two Modes of Synergistic Induction of Apoptosis by Mapatumumab and Oxaliplatin in Combination with Hyperthermia in Human Colon Cancer Cells

Colorectal cancer is the third leading cause of cancer-related mortality in the world-- the main cause of death from colorectal cancer is hepatic metastases, which can be treated with isolated hepatic perfusion (IHP). Searching for the most clinically relevant approaches for treating colorectal metastatic disease by isolated hepatic perfusion (IHP), we developed the application of oxaliplatin concomitantly with hyperthermia and humanized death receptor 4 (DR4) antibody mapatumumab (Mapa), and investigated the molecular mechanisms of this multimodality treatment in human colon cancer cell lines CX-1 and HCT116 as well as human colon cancer stem cells Tu-12, Tu-21 and Tu-22. We showed here, in this study, that the synergistic effect of the multimodality treatment-induced apoptosis was caspase dependent and activated death signaling via both the extrinsic apoptotic pathway and the intrinsic pathway. Death signaling was activated by c-Jun N-terminal kinase (JNK) signaling which led to Bcl-xL phosphorylation at serine 62, decreasing the anti-apoptotic activity of Bcl-xL, which contributed to the intrinsic pathway. The downregulation of cellular FLICE inhibitory protein long isoform (c-FLIPL) in the extrinsic pathway was accomplished through ubiquitination at lysine residue (K) 195 and protein synthesis inhibition. Overexpression of c-FLIPL mutant (K195R) and Bcl-xL mutant (S62A) completely abrogated the synergistic effect. The successful outcome of this study supports the application of multimodality strategy to patients with colorectal hepatic metastases who fail to respond to standard chemoradiotherapy that predominantly targets the mitochondrial apoptotic pathway. © 2013 Song et al

A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

Meeting abstrac

Lawson criterion for ignition exceeded in an inertial fusion experiment

For more than half a century, researchers around the world have been engaged in attempts to achieve fusion ignition as a proof of principle of various fusion concepts. Following the Lawson criterion, an ignited plasma is one where the fusion heating power is high enough to overcome all the physical processes that cool the fusion plasma, creating a positive thermodynamic feedback loop with rapidly increasing temperature. In inertially confined fusion, ignition is a state where the fusion plasma can begin "burn propagation" into surrounding cold fuel, enabling the possibility of high energy gain. While "scientific breakeven" (i.e., unity target gain) has not yet been achieved (here target gain is 0.72, 1.37 MJ of fusion for 1.92 MJ of laser energy), this Letter reports the first controlled fusion experiment, using laser indirect drive, on the National Ignition Facility to produce capsule gain (here 5.8) and reach ignition by nine different formulations of the Lawson criterion

Measures of frailty in population-based studies: An overview

Although research productivity in the field of frailty has risen exponentially in recent years, there remains a lack of consensus regarding the measurement of this syndrome. This overview offers three services: first, we provide a comprehensive catalogue of current frailty measures; second, we evaluate their reliability and validity; third, we report on their popularity of use

Benthic Reef Primary Production in Response to Large Amplitude Internal Waves at the Similan Islands (Andaman Sea, Thailand)

Coral reefs are facing rapidly changing environments, but implications for reef ecosystem functioning and important services, such as productivity, are difficult to predict. Comparative investigations on coral reefs that are naturally exposed to differing environmental settings can provide essential information in this context. One prevalent phenomenon regularly introducing alterations in water chemistry into coral reefs are internal waves. This study therefore investigates the effect of large amplitude internal waves (LAIW) on primary productivity in coral reefs at the Similan Islands (Andaman Sea, Thailand). The LAIW-exposed west sides of the islands are subjected to sudden drops in water temperature accompanied by enhanced inorganic nutrient concentrations compared to the sheltered east. At the central island, Ko Miang, east and west reefs are only few hundred meters apart, but feature pronounced differences. On the west lower live coral cover (-38 %) coincides with higher turf algae cover (+64 %) and growth (+54 %) compared to the east side. Turf algae and the reef sand-associated microphytobenthos displayed similar chlorophyll a contents on both island sides, but under LAIW exposure, turf algae exhibited higher net photosynthesis (+23 %), whereas the microphytobenthos displayed reduced net and gross photosynthesis (-19 % and -26 %,respectively) accompanied by lower respiration (-42 %). In contrast, the predominant coral Porites lutea showed higher chlorophyll a tissues contents (+42 %) on the LAIW-exposed west in response to lower light availability and higher inorganic nutrient concentrations, but net photosynthesis was comparable for both sides. Turf algae were the major primary producers on the west side, whereas microphytobenthos dominated on the east. The overall primary production rate (comprising all main benthic primary producers) was similar on both island sides, which indicates high primary production variability under different environmental conditions