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The Insulin-like growth factor (IGF)/IGF-receptor pathway with its scaffolding proteins Insulin Receptor Substrate (IRS)1 and IRS2 are crucial regulators of metabolism and progression in metastatic colorectal cancer (mCRC). The goal of the study was the identification of predictive and prognostic markers among IRS1, IRS2, IGF1 and IGF-1R SNPs in mCRC patients enrolled in the FIRE-3 trial. Four SNPs of IRS (IRS1 rs1801278, rs1801123; IRS2 rs1805097, rs2289046) and four SNPs of IGF1-IGFR1 (rs6214, rs6220, rs2946834, rs2016347) were analyzed by PCR/direct-sequencing in the FIRE-3 trial. The relation of SNPs with PFS and OS was evaluated through Kaplan-Meier method and log-rank test in the overall population and in subgroup according to RAS status and treatment arm. In the overall population IRS1 rs1801123 C/- carriers (N= 105) achieved significantly worse OS compared to T/T (N = 464) in univariate (HR = 1.32 [95%CI 1.03-1.70], p = 0.029) and in multivariable. Similar results were observed among RAS wild type. Patients with IGF1 rs2946834 T/- variant (N= 280) achieved improved PFS compared to C/C (N = 257) in univariate (HR = 0.77 [95%CI 0.64-0.92], p = 0.004) and in multivariable. In the RAS wild-type subgroup IGF1 rs2946834 T/- carriers showed better PFS and OS compared to C/C (univariate HR for PFS = 0.65 [95%CI 0.51-0.81], p 0.001; multivariable HR for PFS = 0.63 [95%CI 0.50-0.81], p 0.001). IRS1 rs1801123 SNP was identified as a new prognostic marker for mCRC. IGF1 rs2946834 was confirmed as prognostic factor in the overall population and in RAS wild type patients. Our findings underline the importance of IGF downstream signaling pathway in RAS wild-type mCRC patient.

The Adaptation Design Tool of the Corals & Climate Adaptation Planning (CCAP) project was developed to help coral reef managers incorporate climate‐smart design into their plans, programs, and projects at any stage of planning and implementation. The CCAP Adaptation Design Tool (henceforth referred to as the Design Tool can be used to incorporate climate change adaptation into programs using existing planned actions as a starting point, and also to consider development of additional climate‐smart strategies as needed. Most managers will be working from existing plans responsive to previously established management objectives, with climate change already taken into account to varying degrees.

Creatine kinase (CK) release in response to excessive electrically stimulated contractile activity has been studied in isolated rat soleus muscles. The exacerbation of CK release induced by contractile activity was found to be directly related to the length of time for which the muscle was stimulated and indirectly related to the recovery of force following the end of stimulation. 31P-NMR studies were undertaken using a recirculating superfused muscle preparation and demonstrated that muscles subjected to two different stimulation protocols (stimulation for 0.5 s every 2 s in oxygenated medium or for 1.5 s every 2 s in anoxic medium) had similar falls in ATP content and pH despite a Substantially greater release of CK from the muscles stimulated under anoxia. However, stimulated muscles under anoxia showed a more rapid fall and reduced recovery of phosphocreatine and a greater sustained elevation of inorganic phosphate than muscles in oxygenated medium. It is concluded that only part of the increased loss of CK from muscles stimulated in anoxic medium can be explained by release from cells which have lost energy supplies and therefore that other mechanisms must exist which allow release of CK and other cytosolic enzymes from muscle cells.

Coral reefs are one of the most threatened ecosystems in the world. Rivalling terrestrial rainforests in their biological diversity, and providing major economic benefits from fisheries and tourism, coral reefs ecosystems are of global concern. In addition, reefs provide many vital functions in developing countries, especially in Small Island Developing States. Until recently, stresses caused by human activities – such as land-based sources of pollution and destructive fishing practices – were considered to be the primary dangers to coral reefs. While these problems still persist, the last two decades have seen the emergence of yet another, potentially much greater threat. Coral reefs have been affected, with increasing incidence and severity, by coral bleaching, a phenomenon associated with a variety of stresses, especially increased sea water temperatures. Severe and prolonged bleaching can lead to widespread coral mortality, and the unprecedented coral bleaching and mortality event in 1998 affected large areas of coral reef in the Indo-Pacific. IUCN/Convention on Biological Diversity/USAID/WWF Unpublished

The biochemical, histological and ultrastructural effects of 2,4-dinitrophenol and the calcium ionophore, A23187, on rat soleus muscle incubated in vitro have been examined to test the hypothesis that immunohistochemical techniques can be used to recognize early structural features of fibre damage. In control muscles, despite mild glycogen depletion and a mild reduction in protein synthetic rate in the central portion of the muscle, fibres throughout the muscle appear to be viable with normal cytoskeletal and contractile protein architecture, normal concentrations of high energy phosphates and no creatine kinase efflux. Dinitrophenol causes rapid creatine kinase efflux, extensive loss of immunolabelling for desmin and dystrophin, and abnormal myosin immunolabelling. Creatine kinase efflux and the changes in desmin and dystrophin are reduced by the exclusion of calcium. A23187 causes more gradual creatine kinase efflux associated with changes in myosin immunolabelling, but loss of desmin and dystrophin immunolabelling is restricted to a few of the most peripheral fibres. The results suggest that immunohistochemical methods can be used to reveal differences in the intracellular mechanisms of muscle damage. Although both dinitrophenol and A23187 may act, in part, through calcium-mediated processes, their effects on cytoskeletal proteins differ. Creatine kinase efflux after A23187 may not be due to gross sarcolemmal damage.

(1) A recirculating isolated superfused skeletal muscle preparation has been developed for the study of rat soleus muscles at physiological temperature using 31P Nuclear Magnetic Resonance (NMR). (2) This system has been used to study intracellular muscle high energy phosphate content and pH during experimental damage to the muscle induced by 2,4-dinitrophenol, deoxycholate and the calcium ionophore, A23187. (3) Results indicate that release of intracellular cytosolic enzymes from damaged skeletal muscle may be induced by phosphocreatine (PCr) and adenosine trisphosphate (ATP) depletion, but under certain circumstances intracellular enzymes can be released from skeletal muscle without any fall in muscle PCr or ATP content.

The 31P-NMR technique has been used to assess the intracellular ratios and concentrations of mobile ATP and ADP and the intracellular pH in an insulin-secreting cell line, RINm5F. The single-channel current-recording technique has been used to investigate the effects of changes in the concentrations of ATP and ADP on the gating of nucleotide-dependent K+ channels. Adding ATP to the membrane inside closes these channels. However, in the continued presence of ATP adding ADP invariably leads to the reactivation of ATP-inhibited K+ channels, even at ATP4-/ADP3- concentration ratios greater than 7:1. Interactions between ATP4- and ADP3- seem competitive. An increase in the concentration ratio ATP4-/ADP3- consistently evoked a decrease in the open-state probability of K+ channels; conversely, a decrease in ATP4-/ADP3- increased the frequency of K+ channel opening events. Channel gating was also influenced by changes in the absolute concentrations of ATP4- and ADP3-, at constant free concentration ratios. ADP-evoked stimulation of ATP-inhibited channels did not result from phosphorylation of the channel, as ADP-beta-S, a nonhydrolyzable analog of ADP, not only stimulated but enhanced ADP-induced activation of K+ channels, in the presence of ATP. Similarly, ADP was able to activate K+ channels in the presence of two nonhydrolyzable derivatives of ATP, AMP-PNP and beta gamma methylene ATP.

We describe the use of 31P NMR spectroscopy in the study of metabolic changes related to hypoxia in cultured human tumor cells in vitro. The 31P NMR spectrum can easily distinguish between metabolically active cells, metabolically inactive “dormant” cells, and necrotic cells. A crucial observation was that of the ability of the “dormant” cells to resume active metabolism on incubation with oxygen after long periods of hypoxia. © 1987 Academic Press. Inc.

BACKGROUND Macrophages play a crucial role in the interaction between tumor and immune system, and iNOS is known as a surrogate marker of M1 macrophages activation. The goal of the study was to investigate the role of iNOS polymorphisms as prognostic marker in mCRC patients. MATERIALS AND METHODS Functional significant polymorphisms in the promoter of INOS gene were analyzed by PCR-based and direct DNA sequencing in 4 cohorts of patients receiving bevacizumab based first-line chemotherapy: two evaluation cohorts (TRIBE ARM A and ARM B) and two validation cohorts (FIRE 3 arm A and MOMA). The relation of the SNPs with PFS and OS was evaluated through Kaplan-Meier method and log-rank test. Subgroup analyses according to RAS status were preplanned. RESULTS In the exploratory cohort 1 (TRIBE A), patients with CCTTT any>13repeats (N = 57) showed improved median PFS compared with patients carrying the ≤13/≤13 repeats variant (N = 152) (HR, 0.64; 95%CI 0.44-0.92, p = 0.010). Similar results were shown adopting the >26repeats/≤26 repeats (HR, 0.56; 95%CI 0.36-0.87, p = 0.005). In RAS mutant, patient with any>13 repeats (N = 24) had improved PFS results compared with those carrying the ≤13/≤13 repeats variant (N = 81) (HR, 0.51; 95%CI 0.30-0.87, p = 30.009). Similar results were found adopting the >26 repeats/≤26 repeats cut off: (HR, 0.52; 95%CI 0.27-0.98, p = 0.035). These data were partially confirmed in the exploratory cohort 2 (TRIBE B): a better median PFS was observed in patients with >26 repeats vs ≤26 repeats (N = 205) patients. However, these data were not confirmed in the two validation cohorts. CONCLUSION We failed to replicate the exploratory findings in both validation sets. The CCTTT polymorphic region of the INOS gene does not predict outcome in mCRC receiving bevacizumab based first line chemotherapy. Further investigations are needed to reveal mechanisms between tumor, immune system and chemotherapy response.

The mass extinction characterizing the Permian/Triassic boundary (PTB; ~ 252 Ma) corresponds to a major faunal shift between the Palaeozoic and the Modern evolutionary fauna. The temporal, spatial, environmental, and ecological dynamics of the associated biotic recovery remain highly debated, partly due to the scarce, or poorly-known, Early Triassic fossil record. Recently, an exceptionally complex ecosystem dated from immediately after the Smithian/Spathian boundary (~ 3 myr after the PTB) was reported: the Paris Biota (Idaho, USA). However, the spatiotemporal representativeness of this unique assemblage remained questionable as it was hitherto only reported from a single site. Here we describe three new exceptionally diverse assemblages of the same age as the Paris Biota, and a fourth younger one. They are located in Idaho and Nevada, and are taxonomic subsets of the Paris Biota. We show that the latter covered a region-wide area and persisted at least partially throughout the Spathian. The presence of a well-established marine fauna such as the Paris Biota, as soon as the early Spathian, indicates that the post-PTB biotic recovery and the installation of complex ecosystems probably took place earlier than often assumed, at least at a regional scale.

International audience; In the aftermath of the catastrophic end-Permian mass extinction, the Early Triassic records recurrent perturbations in the carbon isotope signal, most notably during the Smithian and through the Smithian/Spathian Boundary (SSB; ~ 1.5 myr after the Permian/Triassic boundary), which show some of the largest excursions of the Phanerozoic. The late Smithian also corresponds to major biotic turnovers and environmental changes, such as temperature fluctuations, that deeply impacted the recovery after the end-Permian mass extinction. Here we document the paired carbon isotope signal along with an analysis of the trace and major elements at the long-known Hot Springs section (southeastern Idaho, USA). This section records Early Triassic sediments from the Griesbachian-Dienerian up to the lower Spathian. We show that the organic and carbonate δ13C variations mirror the signals identified at a global scale. Particularly, the middle Smithian-SSB event represented by a negative-positive isotopic couplet is well identified and is not of diagenetic origin. We also document a positive excursion potentially corresponding to the Dienerian/Smithian Boundary. Observed Smithian-Spathian excursions are recorded similarly in both the organic and carbonate reservoirs, but the organic matter signal systematically shows unexpectedly dampened variations compared to its carbonate counterpart. Additionally, we show that variations in the net isotopic effect (i.e., Δ13C) probably resulted from a complex set of forcing parameters including either a mixing between terrestrial and marine organic matter depending on the evolution of the depositional setting, or variations in the biological fractionation. We establish that the Δ13C signal cannot be directly related to CO2-driven temperature variations at Hot Springs. Even though the carbon isotope signal mirrors the Early Triassic variations known at the global scale, the Hot Springs signal probably also reflects local influences on the carbon isotopes that are neither diagenetic nor representative of the global exogenic carbon cycle