A phase I study of intravenous liposomal daunorubicin (DaunoXome) in paediatric patients with relapsed or resistant solid tumours

Anthracyclines are widely used in paediatric oncology, but their use is limited by the risk of cumulative cardiac toxicity. Encapsulating anthracyclines in liposomes may reduce cardiac toxicity and possibly increase drug availability to tumours. A phase I study in paediatric patients was designed to establish the dose limiting toxicity (DLT) and maximum tolerated dose (MTD) after a single course of liposomal daunorubicin, ‘DaunoXome', as a 1 h infusion on day 1 of a 21 day cycle. Patients were stratified into two groups according to prior treatment: Group A (conventional) and group B (heavily pretreated patients). Dose limiting toxicity was expected to be haematological, and a two-step escalation was planned, with and without G-CSF support. Pharmacokinetic studies were carried out in parallel. In all, 48 patients aged from 1 to 18 years were treated. Dose limiting toxicity was neutropenia for both groups. Maximum tolerated dose was defined as 155 mg m−2 for Group A and 100 mg m−2 for Group B. The second phase with G-CSF was interrupted because of evidence of cumulative cardiac toxicity. Cardiac toxicity was reported in a total of 15 patients in this study. DaunoXome shares the early cardiotoxicity of conventional anthracyclines in paediatric oncology. This study has successfully defined a haematological MTD for DaunoXome, but the significance of this is limited given the concerns of delayed cardiac toxicity. The importance of longer-term follow-up in patients enrolled into phase I studies has been underestimated previously, and may lead to an under-recognition of important adverse events

Does Pathogen Spillover from Commercially Reared Bumble Bees Threaten Wild Pollinators?

The conservation of insect pollinators is drawing attention because of reported declines in bee species and the ‘ecosystem services’ they provide. This issue has been brought to a head by recent devastating losses of honey bees throughout North America (so called, ‘Colony Collapse Disorder’); yet, we still have little understanding of the cause(s) of bee declines. Wild bumble bees (Bombus spp.) have also suffered serious declines and circumstantial evidence suggests that pathogen ‘spillover’ from commercially reared bumble bees, which are used extensively to pollinate greenhouse crops, is a possible cause. We constructed a spatially explicit model of pathogen spillover in bumble bees and, using laboratory experiments and the literature, estimated parameter values for the spillover of Crithidia bombi, a destructive pathogen commonly found in commercial Bombus. We also monitored wild bumble bee populations near greenhouses for evidence of pathogen spillover, and compared the fit of our model to patterns of C. bombi infection observed in the field. Our model predicts that, during the first three months of spillover, transmission from commercial hives would infect up to 20% of wild bumble bees within 2 km of the greenhouse. However, a travelling wave of disease is predicted to form suddenly, infecting up to 35–100% of wild Bombus, and spread away from the greenhouse at a rate of 2 km/wk. In the field, although we did not observe a large epizootic wave of infection, the prevalences of C. bombi near greenhouses were consistent with our model. Indeed, we found that spillover has allowed C. bombi to invade several wild bumble bee species near greenhouses. Given the available evidence, it is likely that pathogen spillover from commercial bees is contributing to the ongoing decline of wild Bombus in North America. Improved management of domestic bees, for example by reducing their parasite loads and their overlap with wild congeners, could diminish or even eliminate pathogen spillover

Inhibition of HERG1 K+ channel protein expression decreases cell proliferation of human small cell lung cancer cells

HERG (human ether-à-go-go-related gene) K+ currents fulfill important ionic functions in cardiac and other excitable cells. In addition, HERG channels influence cell growth and migration in various types of tumor cells. The mechanisms underlying these functions are still not resolved. Here, we investigated the role of HERG channels for cell growth in a cell line (SW2) derived from small cell lung cancer (SCLC), a malignant variant of lung cancer. The two HERG1 isoforms (HERG1a, HERG1b) as well as HERG2 and HERG3 are expressed in SW2 cells. Inhibition of HERG currents by acute or sustained application of E-4031, a specific ERG channel blocker, depolarized SW2 cells by 10–15 mV. This result indicated that HERG K+ conductance contributes considerably to the maintenance of the resting potential of about −45 mV. Blockage of HERG channels by E-4031 for up to 72 h did not affect cell proliferation. In contrast, siRNA-induced inhibition of HERG1 protein expression decreased cell proliferation by about 50%. Reduction of HERG1 protein expression was confirmed by Western blots. HERG current was almost absent in SW2 cells transfected with siRNA against HERG1. Qualitatively similar results were obtained in three other SCLC cell lines (OH1, OH3, H82), suggesting that the HERG1 channel protein is involved in SCLC cell growth, whereas the ion-conducting function of HERG1 seems not to be important for cell growth

Glioma imaging in Europe: A survey of 220 centres and recommendations for best clinical practice

Objectives: At a European Society of Neuroradiology (ESNR) Annual Meeting 2015 workshop, commonalities in practice, current controversies and technical hurdles in glioma MRI were discussed. We aimed to formulate guidance on MRI of glioma and determine its feasibility, by seeking information on glioma imaging practices from the European Neuroradiology community. Methods: Invitations to a structured survey were emailed to ESNR members (n=1,662) and associates (n=6,400), European national radiologists’ societies and distributed via social media. Results: Responses were received from 220 institutions (59% academic). Conventional imaging protocols generally include T2w, T2-FLAIR, DWI, and pre- and post-contrast T1w. Perfusion MRI is used widely (85.5%), while spectroscopy seems reserved for specific indications. Reasons for omitting advanced imaging modalities include lack of facility/software, time constraints and no requests. Early postoperative MRI is routinely carried out by 74% within 24–72 h, but only 17% report a percent measure of resection. For follow-up, most sites (60%) issue qualitative reports, while 27% report an assessment according to the RANO criteria. A minori

Biogeographical Survey Identifies Consistent Alternative Physiological Optima and a Minor Role for Environmental Drivers in Maintaining a Polymorphism

The contribution of adaptive mechanisms in maintaining genetic polymorphisms is still debated in many systems. To understand the contribution of selective factors in maintaining polymorphism, we investigated large-scale (>1000 km) geographic variation in morph frequencies and fitness-related physiological traits in the damselfly Nehalennia irene. As fitness-related physiological traits, we investigated investment in immune function (phenoloxidase activity), energy storage and fecundity (abdomen protein and lipid content), and flight muscles (thorax protein content). In the first part of the study, our aim was to identify selective agents maintaining the large-scale spatial variation in morph frequencies. Morph frequencies varied considerably among populations, but, in contrast to expectation, in a geographically unstructured way. Furthermore, frequencies co-varied only weakly with the numerous investigated ecological parameters. This suggests that spatial frequency patterns are driven by stochastic processes, or alternatively, are consequence of highly variable and currently unidentified ecological conditions. In line with this, the investigated ecological parameters did not affect the fitness-related physiological traits differently in both morphs. In the second part of the study, we aimed at identifying trade-offs between fitness-related physiological traits that may contribute to the local maintenance of both colour morphs by defining alternative phenotypic optima, and test the spatial consistency of such trade-off patterns. The female morph with higher levels of phenoloxidase activity had a lower thorax protein content, and vice versa, suggesting a trade-off between investments in immune function and in flight muscles. This physiological trade-off was consistent across the geographical scale studied and supports widespread correlational selection, possibly driven by male harassment, favouring alternative trait combinations in both female morphs

Root Herbivore Effects on Aboveground Multitrophic Interactions: Patterns, Processes and Mechanisms

In terrestrial food webs, the study of multitrophic interactions traditionally has focused on organisms that share a common domain, mainly above ground. In the last two decades, it has become clear that to further understand multitrophic interactions, the barrier between the belowground and aboveground domains has to be crossed. Belowground organisms that are intimately associated with the roots of terrestrial plants can influence the levels of primary and secondary chemistry and biomass of aboveground plant parts. These changes, in turn, influence the growth, development, and survival of aboveground insect herbivores. The discovery that soil organisms, which are usually out of sight and out of mind, can affect plant-herbivore interactions aboveground raised the question if and how higher trophic level organisms, such as carnivores, could be influenced. At present, the study of above-belowground interactions is evolving from interactions between organisms directly associated with the plant roots and shoots (e.g., root feeders - plant - foliar herbivores) to interactions involving members of higher trophic levels (e.g., parasitoids), as well as non-herbivorous organisms (e.g., decomposers, symbiotic plant mutualists, and pollinators). This multitrophic approach linking above- and belowground food webs aims at addressing interactions between plants, herbivores, and carnivores in a more realistic community setting. The ultimate goal is to understand the ecology and evolution of species in communities and, ultimately how community interactions contribute to the functioning of terrestrial ecosystems. Here, we summarize studies on the effects of root feeders on aboveground insect herbivores and parasitoids and discuss if there are common trends. We discuss the mechanisms that have been reported to mediate these effects, from changes in concentrations of plant nutritional quality and secondary chemistry to defense signaling. Finally, we discuss how the traditional framework of fixed paired combinations of root- and shoot-related organisms feeding on a common plant can be transformed into a more dynamic and realistic framework that incorporates community variation in species, densities, space and time, in order to gain further insight in this exciting and rapidly developing field

Modeling-Dependent Protein Characterization of the Rice Aldehyde Dehydrogenase (ALDH) Superfamily Reveals Distinct Functional and Structural Features

The completion of the rice genome sequence has made it possible to identify and characterize new genes and to perform comparative genomics studies across taxa. The aldehyde dehydrogenase (ALDH) gene superfamily encoding for NAD(P)+-dependent enzymes is found in all major plant and animal taxa. However, the characterization of plant ALDHs has lagged behind their animal- and prokaryotic-ALDH homologs. In plants, ALDHs are involved in abiotic stress tolerance, male sterility restoration, embryo development and seed viability and maturation. However, there is still no structural property-dependent functional characterization of ALDH protein superfamily in plants. In this paper, we identify members of the rice ALDH gene superfamily and use the evolutionary nesting events of retrotransposons and protein-modeling–based structural reconstitution to report the genetic and molecular and structural features of each member of the rice ALDH superfamily in abiotic/biotic stress responses and developmental processes. Our results indicate that rice-ALDHs are the most expanded plant ALDHs ever characterized. This work represents the first report of specific structural features mediating functionality of the whole families of ALDHs in an organism ever characterized

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

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